低氧运动促进肌组织血管生成的机制
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摘要
研究目的:
通过研究低氧运动对肌组织血管生成低氧反应基因的转录调节、低氧反应基因产物对肌组织血管生成的促进作用、低氧运动肌组织血管的生成机制,来探讨低氧运动促进肌组织血管生成的机制,为低氧训练在运动实践中的运用提供理论依据和应用途径。
研究方法:
应用低氧细胞培养、凝胶迁移率变动实验方法,研究低氧调节培养人脐静脉内皮细胞HIF-1与VEGF、Flt-1 DNA结合活性。应用3×3析因设计试验,采用递增负荷运动训练方案,及低氧和超低氧两种不同程度的递增低氧刺激,在运动中和运动后给予低氧处理,建立大鼠不同运动方式后进行不同程度低氧刺激动物模型,在此基础上,应用血气分析、免疫组织化学、原位杂交及计算机图像分析等方法,研究低氧运动对大鼠动脉血氧合状态的影响,及动脉血氧合程度的下降对肌组织HIF-1α的影响,进而对低氧运动肌组织VEGF、Flt-1基因转录的促进作用;应用酶联免疫吸附检测、免疫组织化学及计算机图像分析及体视学等方法,研究VEGF、Flt-1对低氧运动肌组织血管生成的促进作用;应用透射电镜研究方法,从形态学角度研究低氧运动肌组织血管生成的方式。
结论:
采用不同氧含量的混合气体进行脐静脉内皮细胞培养,为低氧训练肌组织血管生成的离体研究提供了低氧细胞培养模型;应用3×3析因设计试验方法,采用递增负荷跑台运动训练和递增低氧程度低氧刺激,建立了不同低氧处理及运动方式的低氧训练动物实验模型。
单纯低氧(氧含量由18.2kPa逐周下降至15.2 kPa )或超低氧(氧含量由17.4 kPa逐周下降至11.3kPa )处理,不能增加肌组织微血管密度,常氧训练、低氧训练,以及训练后进行低氧处理,可增加肌组织微血管密度。低氧处理与训练方式两种因素对肌组织微血管密度的增加具有协同交互作用,并且低氧处理、训练方式的主效应有差别。从常氧训练与低氧训练微血管数量变化的差异来看,低氧训练对肌组织微血管的影响优于常氧训练。低氧及运动使心肌、骨骼肌组织中微血管密度增加,有利于运动中肌组织对氧、营养物质的摄取,及代谢产物的排出,表明在运动训练中或训练后施以低氧条件刺激,可作为一种增强机体耐缺氧能力的辅助训练手段。
对肌组织毛细血管超微结构的研究发现,低氧运动肌组织血管生成可通过芽生或非芽生的方式进行,这两种血管生成方式中以非芽生方式即套迭式微血管生长方式为主要形式,表明低氧运动可使肌组织在满足能量和代谢方面采用更快、更经济的血管生成方式,促进血管物质交换功能的增强,来提高机体的运动能力。
低氧运动血管生成的转录调节机制为:由于离体情况下,低氧可增加培养人脐静脉内皮细胞中HIF-1与血管生成低氧反应基因VEGF、Flt-1 DNA结合活性,这种结合活性在一定氧张力范围内(培养液中氧分压不高于80.50mmHg,此时混合培养气体中的氧含量为7%)受低氧浓度的调节;在体情况下,低氧及运动可降低动脉血氧合程度,低氧训练是使动脉血氧分压下降的最有效刺激;并且低氧运动可使HIF-1α蛋白、VEGF mRNA、Flt-1 mRNA增加。因此受机体氧合程度的下降,低氧运动可增强肌组织中HIF-1α蛋白表达,低氧和运动肌组织HIF-1α蛋白表达的增加可促进VEGF、Flt-1的基因转录。
低氧运动促进肌组织血管生成的作用机制为:低氧运动可使肌组织血管生成低氧反应基因VEGF、Flt-1的蛋白产物增加,VEGF蛋白产生后,可通过自分泌或旁分泌的方式,与肌组织中血管内皮细胞膜上的Flt-1受体结合,参与肌组织血管生成;低氧、运动以及低氧运动都能使血清VEGF含量减少,而此时肌组织VEGF蛋白含量增加,由于肌组织Flt-1受体含量增加,而增加了肌组织对循环中VEGF的摄取、利用,减少了血清VEGF含量。因此,血清VEGF含量可作为反映机体耐低氧能力的指标。
Objective:
In order to provide a theoretical basis and applied methods for hypoxic training applied in sports practice, this thesis studied the mechanism of hypoxic training promoting angiogenesis on muscular tissue by exploring the effect of hypoxic training on regulating the hypoxic responsive genes on muscular issue, the effect of the hypoxic responsive genes on boosting angiogenesis on muscular issues, and the angiogenesis mechanism of hypoxic training muscular tissue.
Material and Methods:
Hypoxia cell culture and electrophoretic mobility shift assay were applied to study the protein-DNA binding activity of hypoxia induced factor-1 and vascular endothelium growth factor gene, and fms-like tyrosine kinase-1 of human umbilicus vein endothelial cell under hypoxia. 3×3 factorial experiment, progressive treadmill exercise, hypoxia and super-hypoxia increasing by degree were used to establish animal model with different training pattern and different hypoxic stimulus. Thereafter, Blood-gas analysis, in situ hybridization, immunohistochemical technology and computer image processing methods were used to study the effect of hypoxic training on the oxygen binding status of arterial blood, the effect of oxygen binding status of arterial blood on hypoxia induced factor-1αof muscular tissue, and then the promoting effect of hypoxic training on genes transcription of vascular endothelium growth factor and fms-like tyrosine kinase-1. In addition, Enzyme linked immunosorbnent assay, Stereology, immunohistochemical technology and computer image processing methods were used to study the accelerating effect of vascular endothelium growth factor and fms-like tyrosine kinase-1 on hypoxic training angiogenesis of muscular tissue. In the end, transmission electron microscope was applied to study the morphological mode of angiogenesis of hypoxic training muscular tissue.
Conclusions:
Different Oxygen content mixed gases were administered to culture human umbilical vein endothelium cell to found hypoxia cell culture model for ex vivo study of hypoxic training, and an animal model of hypoxic training was successfully established by progressive treadmill exercise and hypoxic stimulus with progressive hypoxia.
Simple hypoxia (hypoxia content from 18.2kPa to 15.2 kPa ) and super- hypoxia (hypoxia content from 17.4 kPa to 11.3kPa ) could not increase density of micro- blood vessel. Normoxic training, hypoxic training, and hypoxic administration after training could increase density of micro- blood vessel. Interaction occurred between hypoxic administration and training pattern, and hypoxic administration and training pattern had different main effects. From the changing of micro- blood vessel, hypoxic training was found to be better than normoxic training to micro- blood vessel on muscular tissue.
In vivo, hypoxia could increase binding activity of HIF-1 of culture human umbilical vein endothelium cell and VEGF、Flt-1 DNA. The binding activity was regulated by oxygen content within a certain range. Ex vivo, hypoxia could decrease arterial blood oxygen binding; hypoxic training was the most efficient stimulus to decrease arterial partial pressure of oxygen, while it could decrease arterial blood oxygen binding to a large degree. The transcription regulation mechanism of angiogenesis of hypoxic training muscular tissue was: affected by the degree of oxygen binding, hypoxic training could increase the protein expression of HIF-1 o?n muscular tissue and the increase could promote the genes transcription of VEGF and Flt-1.
The mechanism of hypoxia responsive genes promoting the angiogenesis of hypoxic training muscular tissue was: hypoxic training could increase the protein of angiogenesis hypoxia responsive genes VEGF and Flt-1, and after VEGF protein was produced, it could secrete by autocrine or by paracrine, combine with Flt-1 receptor on the vascular endothelium cell membrane, and participate in the angiogenesis of muscular tissue. Hypoxia, training, and hypoxic training all could reduce the content of serum VEGF, meanwhile, the proteins of VEGF on muscular tissue increased and the Flt-1 receptors also increased. Therefore, ingestion and utilization of VEGF from circulation was increased on muscular tissue.
Angiogenesis on muscular tissue could be performed by means of sprouting and no-sprouting, among which no-sprouting angiogenesis pattern, i.e. intussusceptive microvascular growth, was the major way, suggesting that muscular tissue could take faster and more economical angiogenesis pattern to satisfy the demands of energy and metabolization.
通过研究低氧运动对肌组织血管生成低氧反应基因的转录调节、低氧反应基因产物对肌组织血管生成的促进作用、低氧运动肌组织血管的生成机制,来探讨低氧运动促进肌组织血管生成的机制,为低氧训练在运动实践中的运用提供理论依据和应用途径。
研究方法:
应用低氧细胞培养、凝胶迁移率变动实验方法,研究低氧调节培养人脐静脉内皮细胞HIF-1与VEGF、Flt-1 DNA结合活性。应用3×3析因设计试验,采用递增负荷运动训练方案,及低氧和超低氧两种不同程度的递增低氧刺激,在运动中和运动后给予低氧处理,建立大鼠不同运动方式后进行不同程度低氧刺激动物模型,在此基础上,应用血气分析、免疫组织化学、原位杂交及计算机图像分析等方法,研究低氧运动对大鼠动脉血氧合状态的影响,及动脉血氧合程度的下降对肌组织HIF-1α的影响,进而对低氧运动肌组织VEGF、Flt-1基因转录的促进作用;应用酶联免疫吸附检测、免疫组织化学及计算机图像分析及体视学等方法,研究VEGF、Flt-1对低氧运动肌组织血管生成的促进作用;应用透射电镜研究方法,从形态学角度研究低氧运动肌组织血管生成的方式。
结论:
采用不同氧含量的混合气体进行脐静脉内皮细胞培养,为低氧训练肌组织血管生成的离体研究提供了低氧细胞培养模型;应用3×3析因设计试验方法,采用递增负荷跑台运动训练和递增低氧程度低氧刺激,建立了不同低氧处理及运动方式的低氧训练动物实验模型。
单纯低氧(氧含量由18.2kPa逐周下降至15.2 kPa )或超低氧(氧含量由17.4 kPa逐周下降至11.3kPa )处理,不能增加肌组织微血管密度,常氧训练、低氧训练,以及训练后进行低氧处理,可增加肌组织微血管密度。低氧处理与训练方式两种因素对肌组织微血管密度的增加具有协同交互作用,并且低氧处理、训练方式的主效应有差别。从常氧训练与低氧训练微血管数量变化的差异来看,低氧训练对肌组织微血管的影响优于常氧训练。低氧及运动使心肌、骨骼肌组织中微血管密度增加,有利于运动中肌组织对氧、营养物质的摄取,及代谢产物的排出,表明在运动训练中或训练后施以低氧条件刺激,可作为一种增强机体耐缺氧能力的辅助训练手段。
对肌组织毛细血管超微结构的研究发现,低氧运动肌组织血管生成可通过芽生或非芽生的方式进行,这两种血管生成方式中以非芽生方式即套迭式微血管生长方式为主要形式,表明低氧运动可使肌组织在满足能量和代谢方面采用更快、更经济的血管生成方式,促进血管物质交换功能的增强,来提高机体的运动能力。
低氧运动血管生成的转录调节机制为:由于离体情况下,低氧可增加培养人脐静脉内皮细胞中HIF-1与血管生成低氧反应基因VEGF、Flt-1 DNA结合活性,这种结合活性在一定氧张力范围内(培养液中氧分压不高于80.50mmHg,此时混合培养气体中的氧含量为7%)受低氧浓度的调节;在体情况下,低氧及运动可降低动脉血氧合程度,低氧训练是使动脉血氧分压下降的最有效刺激;并且低氧运动可使HIF-1α蛋白、VEGF mRNA、Flt-1 mRNA增加。因此受机体氧合程度的下降,低氧运动可增强肌组织中HIF-1α蛋白表达,低氧和运动肌组织HIF-1α蛋白表达的增加可促进VEGF、Flt-1的基因转录。
低氧运动促进肌组织血管生成的作用机制为:低氧运动可使肌组织血管生成低氧反应基因VEGF、Flt-1的蛋白产物增加,VEGF蛋白产生后,可通过自分泌或旁分泌的方式,与肌组织中血管内皮细胞膜上的Flt-1受体结合,参与肌组织血管生成;低氧、运动以及低氧运动都能使血清VEGF含量减少,而此时肌组织VEGF蛋白含量增加,由于肌组织Flt-1受体含量增加,而增加了肌组织对循环中VEGF的摄取、利用,减少了血清VEGF含量。因此,血清VEGF含量可作为反映机体耐低氧能力的指标。
Objective:
In order to provide a theoretical basis and applied methods for hypoxic training applied in sports practice, this thesis studied the mechanism of hypoxic training promoting angiogenesis on muscular tissue by exploring the effect of hypoxic training on regulating the hypoxic responsive genes on muscular issue, the effect of the hypoxic responsive genes on boosting angiogenesis on muscular issues, and the angiogenesis mechanism of hypoxic training muscular tissue.
Material and Methods:
Hypoxia cell culture and electrophoretic mobility shift assay were applied to study the protein-DNA binding activity of hypoxia induced factor-1 and vascular endothelium growth factor gene, and fms-like tyrosine kinase-1 of human umbilicus vein endothelial cell under hypoxia. 3×3 factorial experiment, progressive treadmill exercise, hypoxia and super-hypoxia increasing by degree were used to establish animal model with different training pattern and different hypoxic stimulus. Thereafter, Blood-gas analysis, in situ hybridization, immunohistochemical technology and computer image processing methods were used to study the effect of hypoxic training on the oxygen binding status of arterial blood, the effect of oxygen binding status of arterial blood on hypoxia induced factor-1αof muscular tissue, and then the promoting effect of hypoxic training on genes transcription of vascular endothelium growth factor and fms-like tyrosine kinase-1. In addition, Enzyme linked immunosorbnent assay, Stereology, immunohistochemical technology and computer image processing methods were used to study the accelerating effect of vascular endothelium growth factor and fms-like tyrosine kinase-1 on hypoxic training angiogenesis of muscular tissue. In the end, transmission electron microscope was applied to study the morphological mode of angiogenesis of hypoxic training muscular tissue.
Conclusions:
Different Oxygen content mixed gases were administered to culture human umbilical vein endothelium cell to found hypoxia cell culture model for ex vivo study of hypoxic training, and an animal model of hypoxic training was successfully established by progressive treadmill exercise and hypoxic stimulus with progressive hypoxia.
Simple hypoxia (hypoxia content from 18.2kPa to 15.2 kPa ) and super- hypoxia (hypoxia content from 17.4 kPa to 11.3kPa ) could not increase density of micro- blood vessel. Normoxic training, hypoxic training, and hypoxic administration after training could increase density of micro- blood vessel. Interaction occurred between hypoxic administration and training pattern, and hypoxic administration and training pattern had different main effects. From the changing of micro- blood vessel, hypoxic training was found to be better than normoxic training to micro- blood vessel on muscular tissue.
In vivo, hypoxia could increase binding activity of HIF-1 of culture human umbilical vein endothelium cell and VEGF、Flt-1 DNA. The binding activity was regulated by oxygen content within a certain range. Ex vivo, hypoxia could decrease arterial blood oxygen binding; hypoxic training was the most efficient stimulus to decrease arterial partial pressure of oxygen, while it could decrease arterial blood oxygen binding to a large degree. The transcription regulation mechanism of angiogenesis of hypoxic training muscular tissue was: affected by the degree of oxygen binding, hypoxic training could increase the protein expression of HIF-1 o?n muscular tissue and the increase could promote the genes transcription of VEGF and Flt-1.
The mechanism of hypoxia responsive genes promoting the angiogenesis of hypoxic training muscular tissue was: hypoxic training could increase the protein of angiogenesis hypoxia responsive genes VEGF and Flt-1, and after VEGF protein was produced, it could secrete by autocrine or by paracrine, combine with Flt-1 receptor on the vascular endothelium cell membrane, and participate in the angiogenesis of muscular tissue. Hypoxia, training, and hypoxic training all could reduce the content of serum VEGF, meanwhile, the proteins of VEGF on muscular tissue increased and the Flt-1 receptors also increased. Therefore, ingestion and utilization of VEGF from circulation was increased on muscular tissue.
Angiogenesis on muscular tissue could be performed by means of sprouting and no-sprouting, among which no-sprouting angiogenesis pattern, i.e. intussusceptive microvascular growth, was the major way, suggesting that muscular tissue could take faster and more economical angiogenesis pattern to satisfy the demands of energy and metabolization.
引文
成令忠,钟翠平,蔡文琴. 第1版.现代组织学.上海:上海科学技术文献出版社,2003:680-689.
郭祖超.医学统计学. 第1版.北京:人民军医出版社,1999:125-126.
胡良平.医学统计应用错误的诊断与释疑.第1版.北京:军事医学科学出版社,1999:83-84.
卢纹岱.SPSS for Windows统计分析.第1版.北京:电子工业出版社,2000:250-261.
蒙可马利[美国]著.汪仁官 陈荣昭译.现代外国统计学优秀著作译丛:实验设计与分析.第3版.北京:中国统计出版社,1998:217-241.
申洪,沈忠英.实用生物体视学技术. 第1版.广州:中山大学出版社,1991:64-86. 张文彤.世界优秀统计工具SPSS 11.0统计分析教程(基础篇). 第1版.北京:希望电子出版社,2002:230-237.
Adair TH, Gay WJ, and Montani JP. (1990). Growth regulation of the vasculature system: evidence for a metabolic hypothesis. Am J Physiol Regulatory Integrative Comp Physiol. 259: R393–R404.
Asano M, Kaneoka K, Nomura T, Asano K, Sone H, Tsurumaru K, Yamashita K, Matsuo K, Suzuki H, Okuda Y. (1998). Increase in serum vascular endothelial growth factor levels during altitude training. Acta Physiol Scand. 162 (4): 455-459.
Banchero N. (1987). Cardiovascular responses to chronic hypoxia. Annu Rev Physiol. 49: 465-476.
Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR, Smith SK. (1995 ). Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 87 (7): 506-516.
Booth FW and Thomason DB. (1991). Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev. 71: 541–585.
Breen EC, Johnson EC, Wagner H, Tseng HM, Sung LA, and Wagner PD. (1996). Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol. 81: 355–361.
Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM. (1996). Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest. 97: 469-476.
Brown MD. (2003). Exercise and coronary vascular remodelling in the healthy heart. Exp Physiol. 88:645-658.
Cambier C, Clerbaux T, Detry B, Marville V, Frans A, Gustin P. (2002). Blood oxygen binding in hypoxaemic calves. Vet Res. 33 (3): 283-290.
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394 485-490.
Cerretelli P and Hoppeler H. (1996). Morphologic and metabolic responses to chronic hypoxia: the muscle system. In: Handbook of Physiology: Environmental Physiology. Bethesda, MD: Am. Physiol. 2: 1155–1181.
Chow NH, Hsu PI, Lin XZ, Yang HB, Chan SH, Cheng KS, Huang SM, Su IJ. (1997). Expression of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: an immunohistochemical study. Hum Pathol. 28 (6): 698-703.
Cosmas AC, Kernan K, Buck E, Fernhall B, Manfredi TG. (1997). Exercise and dietary cholesterol alter rat myocardial capillary ultrastructure. Eur J Appl Physiol Occup Physiol. 75: 62-67. Desplanches D, Hoppeler H, Linossier MT, Denis C, Claassen H, Dormios D, Lacour JR, and Geyssant A. (1993). Effects of training in normoxia and normobaric hypoxia on human muscle ultrastructure. Pflu¨ gers Arch. 425: 263–267.
Desplanches D, Hoppeler H, Tu¨ scher L, Mayet MH, Spielvogel H, Ferretti G, Kayser B, Leuenberger M, Gru¨ nenfelder A, Favier R. (1996). Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia. J Appl Physiol. 81 (5): 1946–1951.
Djonov V, Schmid M, Tschanz SA, Burri PH. (2000). Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ Res. 86 (3): 286-292.
Djonov V, Baum O, Burri PH. (2003). Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res. 314 (1): 107-117.
Durand F, Mucci P, Prefaut C. (2000). Evidence for an inadequate hyperventilation inducing arterial hypoxemia at submaximal exercise in all highly trained endurance athletes. Med Sci Sports Exerc. 32 (5): 926-932.
Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O_Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. (2001). elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 107: 143-154.
Ferrara N, Henzel WJ. (1989). Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 161 (2): 851-858.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, and Semenza GL. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16: 4604-4613.
Gavin TP, Derchak PA, Stager JM. (1998), Ventilation's role in the decline in VO2max and SaO2 in acute hypoxic exercise. Med Sci Sports Exerc. 30 (2): 195-199.
Gavin TP, Spector DA, Wagner H, Breen EC, and Wagner PD. (2000). Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise. J Appl Physiol. 88: 1192–1198.
Geiser J, Vogt M, Billeter R, Zuleger C, Belforti F, Hoppeler H. (2001). Training high--living low: changes of aerobic performance and muscle structure with training at simulated altitude. Int J Sports Med. 22 (8): 579-585.
Gerber HP, Condorelli F, Park J, and Ferrara N. (1997). Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. J Biol Chem. 272: 23659–23667.
Green HJ, Sutton JR, Wolfel EE, Reeves JT, Butterfield GE, Brooks GA. (1992). Altitude acclimatization and energy metabolic adaptations in skeletal muscle during exercise. J Appl Physiol. 73(6): 2701-8.
Green H, MacDougall J, Tarnopolsky M, and Melissa NL. (1999). Downregulation of Na1-K1-ATPase pumps in skeletal muscle with training in normobaric hypoxia. J Appl Physiol. 86: 1745– 1748.
Guillemin K, Krasnow MA. (1997). The hypoxic response: huffing and HIFing. Cell. 89 (1): 9-12.
Gunga HC, Kirsch K, Rocker L, Behn C, Koralewski E, Davila EH, Estrada MI, Johannes B, Wittels P, Jelkmann W. (1999). Vascular endothelial growth factor in exercising humans under different environmental conditions. Eur J Appl Physiol Occup Physiol. 79 (6): 484-490.
Gustafsson T, Knutsson A, Puntschart A, Kaijser L, Nordqvist AC, Sundberg CJ, (2002). Jansson E. Increased expression of vascular endothelial growth factor in human skeletal muscle in response to short-term one-legged exercise training. Pflugers Arch. 444 (6): 752-759.
Gute D, Laughlin MH, and Amann JF. (1994). Regional changes in capillary supply in skeletal muscle of interval-sprint and lowintensity, endurance-trained rats. Microcirculation. 1: 183–193.
Hogenesch JB., Chan WK, Jackiw VH, Brown RC, GU YZ, Pray-Grant M, Perdew GH. Bradfield CA. (1997). Characterization of a subset of the basic-helix–loop–helix- PAS superfamily that interacts with components of the dioxin signaling pathway. J. biol. Chem. 272: 8581–8593.
Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P. (1990). Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 11 Suppl 1: S3-9.
Hoppeler H, Vogt M. (2001). Muscle tissue adaptations to hypoxia. The Journal of Experimental Biology. 204: 3133–3139.
Huang LE, Arany Z, Livingston DM, and Bunn HF. (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit. J Biol Chem. 271: 32253–32259.
Huang Q, Gao Y, Shi J, Liu F, Cao L, Sun B. (2000). Effects of hypoxia alone or exercise combined on capillarization of rat gastrocnemius muscle and its mechanism. Zhonghua Bing Li Xue Za Zhi. 29 (6): 439-442.
Hudlicka O, Brown M, and Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol Rev. 72: 369–417.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 292:5516 464-468.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim Av, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. (2001 ). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 292:5516 468-472.
Jeziorska M, Woolley DE.(1999). Neovascularization in early atherosclerotic lesions of human carotid arteries: its potential contribution to plaque development. Hum Pathol. 30 (8): 919-925.
Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. (1996). Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem Jul 26 271:30 17771-17778.
Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, and Poellinger L. (1998). Signal transduction in hypoxic cells: inducible nuclear localization and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1a. Embo J. 17: 6573–6586.
Kallio PJ, Wilson WJ, O’Brien S, Makino Y, and Poellinger L. (1999). Regulation of the hypoxia- inducible transcription factor 1 alpha by the ubiquitin-proteasome pathway. J Biol Chem. 274, 6519–6525.
Ladoux A, Frelin C. (1993 ). Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun. 195 (2): 1005-1010.
Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. (2002). Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 295: 5556 858-861.
Lash JM and Bohlen HG. (1992). Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training. J Appl Physiol. 72: 2052–2062.
Levine, D., & Stray-Gundersen, J. (1992). A practical approach to altitude training: Where to live and train for the optimal performance enhancement. Inter J Sports Med. 13: S209-S212.
Levine, D, & Stray-Gundersen,J. (1997). Living high-training low: Effect of moderate altitude acclimatization with low altitude on performance. J Appl Physiol. 83: 102-112.
Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M. (1996). VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol. 270(5 Pt 2): H1803-811.
Liu Y, Cox SR, Morita T, Kourembanas S. (1995). Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5' enhancer. Circ Res. 77 (3): 638-643.
Macdougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, Young P, Houston CS. (1991). Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 142 (3): 421-427.
Man'kovs'ka IM, Liabakh KH. (2003). Oxygen transport in skeletal muscles working with its maximum consumption during hypoxemia(abstract). Fiziol Zh. 49(3):75-79.
Melissa L, Macdougall JD, Tarnopolsky MA, Cipriano N, and Green HJ. (1997). Skeletal muscle adaptations to training under normobaric hypoxic versus normoxic conditions. Med Sci Sports Exerc. 29: 238–243.
Moravec M, Turek Z, Moravec J. (2002). Persistence of neoangiogenesis and cardiomyocyte divisions in right ventricular myocardium of rats born and raised in hypoxic conditions. Basic Res Cardiol. 97(2): 153-160.
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, Yamamoto H. (1995). Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia- induced proliferation of endothelial cells and pericytes. J Biol Chem. 270: 28316-28324.
Olfert, I. Mark, Ellen C. Breen, Odile Mathieu- Costello, and Peter D. Wagner. (2001). Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol. 91: 1176–1184.
Patan S, Tanda S, Roberge S, Jones RC, Jain RK, Munn LL. (2001a ). Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation. Circ Res. 89 (8): 732-739.
Patan S, Munn LL, Tanda S, Roberge S, Jain RK, Jones RC. (2001b ). Vascular morphogenesis and remodeling in a model of tissue repair: blood vessel formation and growth in the ovarian pedicle after ovariectomy. Circ Res. 89 (8): 723-731.
Patan S. (2004). Vasculogenesis and angiogenesis. Cancer Treat Res. 117: 3-32.
Rice AJ, Scroop GC, Gore CJ, Thornton AT, Chapman MA, Greville HW, Holmes MD, Scicchitano R.( 1999). Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake. Eur J Appl Physiol Occup Physiol. 79(4): 353-359.
Richardson, RS, Noyszewski EA, Kendrick KF, Leigh JS, and Wagner PD. (1995). Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J. Clin. Invest. 96: 1916–1926.
Richardson RS, Wagner H, Mudaliar SR, Saucedo E, Henry R, Wagner PD. ( 2000). Exercise adaptation attenuates VEGF gene expression in human skeletal muscle. Am J Physiol Heart Circ Physiol. 279 (2): H772-8.
Roach RC, Koskolou MD, Calbet JA, Saltin B.( 1999). Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans. Am J Physiol. 276(2 Pt 2): H438-45.
Ryan HE, Lo J, and Johnson RS. (1998). HIF-1a is required for solid tumor formation and embryonic vascularization. Embo J. 17: 3005–3015.
Sandner P, Wolf K, Bergmaier U, Gess B, Kurtz A.(1997a). Hypoxia and cobalt stimulate vascular endothelial growth factor receptor gene expression in rats. Pflugers Arch. 433 (6): 803-8.
Sandner P, Wolf K, Bergmaier U, Gess B, and Kurtz A. (1997b). Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro. Kidney Int. 51: 448–453.
Semenza GL, Wang GL. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 12: 5447-5454.
Semenza GL, Jiang B-H, Leung SW, Passantino R, Concordet J-P, Maire P, and Giallongo A. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 271, 32529–32537.
Shweiki D, Itin A, Soffer D, Keshet E. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 359(6398):843-5.
Sillau A and Banchero N. (1977). Effects of hypoxia on capillary density and fiber composition in rat skeletal muscle. Pflu¨ gers Arch. 370: 227–232.
Sosa Leon L, Hodgson DR, Evans DL, Ray SP, Carlson GP, Rose RJ. (2002). Hyperhydration prior to moderate-intensity exercise causes arterial hypoxaemia. Equine Vet J Suppl. 34: 425-9.
Suzuki J, Gao M, Batra S, and Koyama T. (1997). Effects of treadmill training on the arteriolar and venular portions of capillary in soleus muscle of young and middle-aged rats. Acta Physiol Scand. 159 (2): 113-121.
Tagarakis CV, Bloch W, Hartmann G, Hollmann W, Addicks K. ( 2000 ). Testosterone-propionate impairs the response of the cardiac capillary bed to exercise. Med Sci Sports Exerc. 32(5):946-953.
Takagi H, King GL, Robinson GS, Ferrara N, and Aiello LP. (1996). Hypoxic induction of VEGF is mediated by adenosine through A2 receptors and elevation of cAMP in retinal pericytes and endothelial cells. Invest Opthalmol Vis Sci. 37: 2165–2176.
Terrados N, Jansson E, Sylven C, and Kaijser L. (1990). Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? J Appl Physiol. 68: 2369–2372.
Tian, H., Mcknight, S. L. Russell, D. W. (1997). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11: 72–82.
Vogt, M., A. Puntschart, J. Geiser, C. Zuleger, R. Billeter, H. Hoppeler. (2001). Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. 91: 173–182.
Wang GL and Jiang BH. (1995a). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-Pas heterodimer regulated by cellular O2 tension. Genetics. 92: 5510–5514.
Wang GL, Jiang BH, Semenza GL. (1995b ). Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun. 212:2 550-556.
Wenger, R. H. and Gassmann, M. (1997). Oxygen(es) and the hypoxia-inducible factor-1. Biol. Chem. 378: 609–616.
White FC, Bloor CM, McKirnan MD, Carroll SM. (1998). Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart. J Appl Physiol. 85(3): 1160-1168.
Wood SM, Wiesener MS, Yeates KM et al. (1998). Selection and analysis of a mutant cell line defective in the hypoxia- inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of Hif- 1 alpha- dependent and -independent hypoxia-inducible gene expression. J Biol Chem. 273: 8360- 8368.
Zhou YD, Barnard M, Tian, Hli X, Ring, HZ, Francke, U, Shelton, J, Richardson, J, Russell, DW Mcknight, SL. (1997). Molecular characterization of two mammalian bHLHPAS domain proteins selectively expressed in the central nervous system. Proc natn Acad Sci. 94: 713–718.
Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM. (1996). An essential role for p300/CBP in the cellular response to hypoxia. Proc natn Acad Sci. 93: 12969-12973.
Asano M. (1998). Increase in serum vascular endothelial growth factor levels during altitude training. Acta Physiol Scand . 162(4): 455-459.
Banchero N. (1987). Cardiovascular responses to chronic hypoxia. Annu Rev Physiol. 49: 65-476.
Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. (1999). Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 13(1): 64-75.
Booth FW ,Thomason DB. (1991). Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev. 71: 541-585.
Breen EC, Johnson EC, Wagner H, Tseng HM, Sung LA, Wagner PD. (1996). Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol. 81: 355-361.
Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM. (1996). Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest. 97: 469-476.
Brown MD. (2003a). Exercise and coronary vascular remodelling in the healthy heart. Exp Physiol . 88: 645-658.
Brown MD. (2003b). Exercise and vascular remodeling. J Physiol. 547P SA18.
Brutsaert TD, Gavin TP, Fu Z, Breen EC, Tang K, Mathieu-Costello O, Wagner PD. (2002). Regional differences in expression of VEGF mRNA in rat gastrocnemius following 1 hr exercise or electrical stimulation. BMC physiology. 2: 8.
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394: 485-490.
Cerretelli P , Hoppeler H. (1996). Morphologic and metabolic responses to chronic hypoxia: the muscle system. In: Handbook of Physiology: Environmental Physiology. Bethesda, MD: Am. Physiol Soc., vol. II, chapt. 50: 1155-1181.
Claffey KP, Shih SC, Mullen A, Dziennis S, Cusick JL, Abrams KR, Lee SW, Detmar M. (1998). Identification of a human VPF/VEGF 39 untranslated region mediating hypoxiainduced mRNA stability. Mol Biol Cell. 9: 469-481.
Cosmas AC, Kernan K, Buck E, Fernhall B, Manfredi TG. (1997). Exercise and dietary cholesterol alter rat myocardial capillary ultrastructure. Eur J Appl Physiol Occup Physiol. 75: 62-67. Desplanches D, Hoppeler H, Linossier MT, Denis C, Claassen H, Dormios D, Lacour JR, Geyssant A. (1993). Effects of training in normoxia and normobaric hypoxia on human muscle ultrastructure. Pflu¨ gers Arch. 425: 263-267.
Desplanches DH, Hoppeler L, Tu¨ scher MH, Mayet H, Spielvogel G, Ferretti B, Kayser M, Leuenberger A, Gru¨ nenfelder R, Favier. (1996). Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia. J Appl Physiol. 81(5): 1946-1951.
Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y. (1999). Molecular mechanisms of transcription activation by HLF and HIF1a in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. 18: 1905-1914.
Esbjo¨ rnsson ME, Jansson CJ, Sundberg C, Sylven O,Eiken A, Nygren, Kaijser L. (1993). Muscle fibre types and enzyme activities after training with local leg ischaemia in man. Acta Physiol Scand. 148: 233-241.
Fong GH, Rossant J, Gerenstein M, Breitman M. (1995). Role of Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 376: 66-67.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16: 4604-4613.
Gavin TP, Spector DA, Wagner H, Breen EC, Wagner PD. (2000a). Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise. J Appl Physiol. 88: 1192-1198.
Gavin TP, Wagner H, Wagner PD. (2000b). VEGF receptor (FLT-1) mRNA response to acute exercise and nitric oxide synthase inhibition (Abstract). FASEB J. 14: A324.
Geiser J, Vogt M, Billeter R, Zuleger C, Belforti F, Hoppeler H. ( 2001). Training high--living low: changes of aerobic performance and muscle structure with training at simulated altitude. Int J Sports Med. 22(8): 579-585.
Gerber HP, Condorelli F, Park J, Ferrara N. (1997). Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. J Biol Chem. 272: 23659-23667.
Green H, MacDougall J, Tarnopolsky M, Melissa NL. (1999). Downregulation of Na1-K1- ATPase pumps in skeletal muscle with training in normobaric hypoxia. J Appl Physiol. 86: 1745- 1748.
Green HJ, Sutton JR, Wolfel EE, Reeves JT, Butterfield GE, Brooks GA. (1992). Altitude acclimatization and energy metabolic adaptations in skeletal muscle during exercise. J Appl Physiol. 73(6): 2701-2708.
Guillemin K, Krasnow MA. (1997). The hypoxic response: huffing and HIFing. Cell. 89(1): 9-12. Gustafsson T, Puntschart A, Kaijser L, Jansson E, Sundberg CJ. (1999). Exercise-induced expression of angiogenesisrelated transcription and growth factors in human skeletal muscle. Am J Physiol Heart Circ Physiol. 276: H679-685.
Gute D, Laughlin MH, Amann JF. (1994). Regional changes in capillary supply in skeletal muscle of interval-sprint and lowintensity, endurance-trained rats. Microcirculation. 1: 183-193.
Hogenesch JB, Chan WK, Jackiw VH, Brown RC, GU YZ, Pray-Grant M, Perdew G H, Bradfield CA. (1997). Characterization of a subset of the basic-helix–loop–helix- PAS superfamily that interacts with components of the dioxin signaling pathway. J biol Chem. 272: 8581-8593.
Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P. (1990). Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 1: S3-9.
Hoppeler H, Desplanches D. (1992). Muscle structural modifications in hypoxia. Int J Sports Med. 1: S166-S168.
Hoppeler H. (1999).Vascular growth in hypoxic skeletal muscle. Adv Exp Med Biol. 474: 277-286.
Huang LE, Arany Z, Livingston DM, Bunn HF. (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit. J Biol Chem. 271: 32253-32259.
Hudlicka O, Brown M, Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol Rev. 72: 369-417.
Iervolino AD, Trisciuoglio. (2002). Bcl-2 overexpression in human melanoma cells increases angiogenesis through VEGF mRNA stabilization and HIF-1-mediated transcriptional activity. The Faseb Journal : Official Publication of the Federation of American Societies For Experimental Biology. 16 (11): 1453-5.
Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. (1998). Signal transduction in hypoxic cells: inducible nuclear localization and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1a. EMBO J. 17: 6573-6586.
Kallio PJ, Wilson WJ, O’Brien S, Makino Y, Poellinger L. (1999). Regulation of the hypoxia-inducible transcription factor 1 alpha by the ubiquitin-proteasome pathway. J Biol Chem 274: 6519-6525.
Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura TD,_Acquisto F, Addeo R, Makuuchi M, Esumi H. ( 2000). Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood. 95: 1189-1197.
Lash JM, Bohlen HG. (1992). Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training. J Appl Physiol. 72: 2052-2062.
Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. ( 2001). HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 21:12 3995- 4004.
Levy AP, Levy NS, Wegner S, Goldberg MA. (1995). Transcriptional regulation of rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 270: 13333-13340.
Lewis AM, Mathieu-Costello O, Mc-Millan PJ, Gilbert RD.( 1999). Effects of long-term, high-altitude hypoxia on the capillarity of the ovine fetal heart. Am J Physiol. 277: H756-762.
Liu Y, Christou H, Morita T, Laughner E, Semenza GL, Kourembanas S.( 1998). Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5' enhancer. J Biol Chem. 273: 24 15257-15262.
Macdougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, Young P, Houston CS. (1991). Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 142(3): 421-427.
Martin C, Yu AY, Jiang BH, Davis L, Kimberly D, Hohimer AR, Semenza GL. (1998). Cardiac hypertrophy in chronically anemic fetal sheep: increased vascularization is associated with increased myocardial expression of vascular endothelial growth factor and hypoxia-inducible factor 1. Am J Obstet Gynecol. 178: 527-534.
Melissa L, Macdougall JD, Tarnopolsky MA, Cipriano N, Green HJ. (1997). Skeletal muscle adaptations to training under normobaric hypoxic versus normoxic conditions. Med Sci Sports Exerc. 29: 238-243.
Moravec M, Turek Z, Moravec J. (2002). Persistence of neoangiogenesis and cardiomyocyte divisions in right ventricular myocardium of rats born and raised in hypoxic conditions. Basic Res Cardiol 97(2): 153-160.
Neufer PD, Ordway GA, Williams RS. (1998). Transient regulation of c-fos, aB-crystallin, and hsp70 in muscle during recovery from contractile activity. Am J Physiol Cell Physiol. 274: C341-C346.
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, Yamamoto H. (1995). Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem. 270: 28316-28324.
Oelz O, Howald H, Di Prampero PE, Hoppeler H, Claassen H, Jenni R, Buhlmann A, Ferretti G, Bruckner JC, Veicsteinas A. (1986). Physiological profile of world-class high-altitude climbers. J Appl Physiol 60(5): 1734-1742.
Olfert IM, Breen EC, MathieuCostello O, Wagner PD. (2001a). Chronic hypoxia attenuates resting and exercise-induced VEGF, f lt-1, and f lk-1 mRNA levels in skeletal muscle. J Appl Physiol. 90: 1532-1538.
Olfert IM, Mark, Ellen C, Breen, Odile Mathieu, Costello, Peter D, Wagner. (2001b). Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol. 91: 1176-1184.
Osada M, Imaoka S, Sugimoto T, Hiroi T, Funae Y. (2002). NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1. J Biol Chem . 277 (26) : 23367-23373.
Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA. (1999). Hypoxia inducible factor 1a is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci. 40: 182-189.
Pelster BA, S?nger M, Siegele, Schwerte T. ( 2003). Influence of swim training on cardiac activity, tissue capillarization, and mitochondrial density in muscle tissue of zebrafish larvae. Am J Physiol Regul Integr Comp Physiol. 85: R339-R347.
Pugh CW, O’Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. (1997). Activation of hypoxia-inducible factor-1; definition of regulatory domains within the a subunit. J Biol Chem. 272: 11205-11214.
Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. (1995). Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J. Clin. Invest. 96, 1916-1926.
Richardson RS, Wagner H, Mudaliar SRD, Henry R, Noyszewski EA, Wagner PD. (1999). Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise. Am J Physiol Heart Circ Physiol. 277: H2247-2252.
Richardson RS, Wagner H, Mudaliar SR, Saucedo E, Henry R, Wagner PD. (2000). Exercise adaptation attenuates VEGF gene expression in human skeletal muscle. Am J Physiol Heart Circ Physiol. 279(2): H772-778.
Ryan HE, Lo J, and Johnson RS. (1998). HIF-1a is required for solid tumor formation and embryonic vascularization. EMBO J. 17: 3005-3015.
Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV. (2002). The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol. 22(6): 1734-1741.
Sanchez, Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C. ( 2001). Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem. 276(42): 38527-38535.
Sandner P, Wolf K, Bergmaier U, Gess B, Kurtz A. (1997a). Hypoxia and cobalt stimulate vascular endothelial growth factor receptor gene expression in rats. Pflugers Arch. 433(6): 803-808.
Sandner P, Wolf K, Bergmaier U, Gess B, Kurtz A. (1997b). Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro. Kidney Int. 51: 448-453.
Semenza GL, Wang GL. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 12: 5447-5454.
Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 271: 32529-32537.
Semenza GL. ( 1998a). Hypoxia-inducible factor 1 and the molecular physiology of oxygen homeostasis. J Lab Clin Med. 131(3): 207-214.
Semenza GL. ( 1998b). Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet. 8: 588-594.
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. ( 1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 376: 65 35 62-3566.
Sillau A , Banchero N. (1977). Effects of hypoxia on capillary density and fiber composition in rat skeletal muscle. Pflu¨ gers Arch. 370: 227-232.
Suzuki J, Gao M, Batra S, Koyama T. (1997). Effects of treadmill training on the arteriolar and venular portions of capillary in soleus muscle of young and middle-aged rats. Acta Physiol Scand. 159 (2): 113-121.
Tagarakis CV, Bloch W, Hartmann G, Hollmann W, Addicks K. (2000). Testosterone-propionate impairs the response of the cardiac capillary bed to exercise. Med Sci Sports Exerc. 32(5): 946-953.
Takagi H, King GL, Robinson GS, Ferrara N, Aiello LP. (1996). Hypoxic induction of VEGF is mediated by adenosine through A2 receptors and elevation of cAMP in retinal pericytes and endothelial cells. Invest Opthalmol Vis Sci. 37: 2165-2176.
Terrados N, Jansson E, Sylven C, Kaijser L. (1990). Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? .J Appl Physiol. 68: 2369-2372. Tian H, Mcknight SL, Russell DW. (1997). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes. 11: 72-82.
Treins C, GiorgettiPeraldi S, Murdaca J, Semenza GL, VanObberghen E.(2002). Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem . 277: 31 27975-27981.
Tuder RM, Flook BE, Voelkel NF. (1995). Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or chronic hypoxia. J Clin Invest. 95: 1798-1807.
Vogt MA, Puntschart J, Geiser C, Zuleger R, Billeter H, Hoppeler. (2001). Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. 91: 173-182.
Wang GL, Jiang BH. (1995a). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-Pas heterodimer regulated by cellular O2 tension. Genetics. 92: 5510-5514.
Wang GL, Jiang BH, Semenza GL. (1995b). Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun. 212: 2550-2 556.
Wenger RH, Gassmann M. (1997). Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem. 378: 609-616.
White FC, Bloor CM, McKirnan MD, Carroll SM. (1998). Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart. J Appl Physiol. 85(3): 1160-1168.
Wood SM, Wiesener MS, Yeates KM. (1998). Selection and analysis of a mutant cell line defective in the hypoxia- inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of Hif- 1alpha-dependent and -independent hypoxia-inducible gene expression. J Biol hem. 273: 8360-8368.
Yin Z, Haynie J, Yang X, Han B, Kiatchoosakun S, Restivo J, Yuan S, Prabhakar NR, Herrup K, Conlon RA, Hoit BD, Watanabe M, Yang YC. (2002). The essential role of Cited2, a negative regulator for HIF-1α, in heart development and neurulation. Proc Natl Acad Sci. 99(16): 10488-10493.
Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, Shelton J, Richardson J, Russell DW, Mcknight SL. (1997). Molecular characterization of two mammalian bHLHPAS domain proteins selectively expressed in the central nervous system. Proc natn Acad Sci. 94: 713-718.
郭祖超.医学统计学. 第1版.北京:人民军医出版社,1999:125-126.
胡良平.医学统计应用错误的诊断与释疑.第1版.北京:军事医学科学出版社,1999:83-84.
卢纹岱.SPSS for Windows统计分析.第1版.北京:电子工业出版社,2000:250-261.
蒙可马利[美国]著.汪仁官 陈荣昭译.现代外国统计学优秀著作译丛:实验设计与分析.第3版.北京:中国统计出版社,1998:217-241.
申洪,沈忠英.实用生物体视学技术. 第1版.广州:中山大学出版社,1991:64-86. 张文彤.世界优秀统计工具SPSS 11.0统计分析教程(基础篇). 第1版.北京:希望电子出版社,2002:230-237.
Adair TH, Gay WJ, and Montani JP. (1990). Growth regulation of the vasculature system: evidence for a metabolic hypothesis. Am J Physiol Regulatory Integrative Comp Physiol. 259: R393–R404.
Asano M, Kaneoka K, Nomura T, Asano K, Sone H, Tsurumaru K, Yamashita K, Matsuo K, Suzuki H, Okuda Y. (1998). Increase in serum vascular endothelial growth factor levels during altitude training. Acta Physiol Scand. 162 (4): 455-459.
Banchero N. (1987). Cardiovascular responses to chronic hypoxia. Annu Rev Physiol. 49: 465-476.
Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, Twentyman PR, Smith SK. (1995 ). Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 87 (7): 506-516.
Booth FW and Thomason DB. (1991). Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev. 71: 541–585.
Breen EC, Johnson EC, Wagner H, Tseng HM, Sung LA, and Wagner PD. (1996). Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol. 81: 355–361.
Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM. (1996). Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest. 97: 469-476.
Brown MD. (2003). Exercise and coronary vascular remodelling in the healthy heart. Exp Physiol. 88:645-658.
Cambier C, Clerbaux T, Detry B, Marville V, Frans A, Gustin P. (2002). Blood oxygen binding in hypoxaemic calves. Vet Res. 33 (3): 283-290.
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394 485-490.
Cerretelli P and Hoppeler H. (1996). Morphologic and metabolic responses to chronic hypoxia: the muscle system. In: Handbook of Physiology: Environmental Physiology. Bethesda, MD: Am. Physiol. 2: 1155–1181.
Chow NH, Hsu PI, Lin XZ, Yang HB, Chan SH, Cheng KS, Huang SM, Su IJ. (1997). Expression of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: an immunohistochemical study. Hum Pathol. 28 (6): 698-703.
Cosmas AC, Kernan K, Buck E, Fernhall B, Manfredi TG. (1997). Exercise and dietary cholesterol alter rat myocardial capillary ultrastructure. Eur J Appl Physiol Occup Physiol. 75: 62-67. Desplanches D, Hoppeler H, Linossier MT, Denis C, Claassen H, Dormios D, Lacour JR, and Geyssant A. (1993). Effects of training in normoxia and normobaric hypoxia on human muscle ultrastructure. Pflu¨ gers Arch. 425: 263–267.
Desplanches D, Hoppeler H, Tu¨ scher L, Mayet MH, Spielvogel H, Ferretti G, Kayser B, Leuenberger M, Gru¨ nenfelder A, Favier R. (1996). Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia. J Appl Physiol. 81 (5): 1946–1951.
Djonov V, Schmid M, Tschanz SA, Burri PH. (2000). Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ Res. 86 (3): 286-292.
Djonov V, Baum O, Burri PH. (2003). Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res. 314 (1): 107-117.
Durand F, Mucci P, Prefaut C. (2000). Evidence for an inadequate hyperventilation inducing arterial hypoxemia at submaximal exercise in all highly trained endurance athletes. Med Sci Sports Exerc. 32 (5): 926-932.
Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O_Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. (2001). elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 107: 143-154.
Ferrara N, Henzel WJ. (1989). Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 161 (2): 851-858.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, and Semenza GL. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16: 4604-4613.
Gavin TP, Derchak PA, Stager JM. (1998), Ventilation's role in the decline in VO2max and SaO2 in acute hypoxic exercise. Med Sci Sports Exerc. 30 (2): 195-199.
Gavin TP, Spector DA, Wagner H, Breen EC, and Wagner PD. (2000). Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise. J Appl Physiol. 88: 1192–1198.
Geiser J, Vogt M, Billeter R, Zuleger C, Belforti F, Hoppeler H. (2001). Training high--living low: changes of aerobic performance and muscle structure with training at simulated altitude. Int J Sports Med. 22 (8): 579-585.
Gerber HP, Condorelli F, Park J, and Ferrara N. (1997). Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. J Biol Chem. 272: 23659–23667.
Green HJ, Sutton JR, Wolfel EE, Reeves JT, Butterfield GE, Brooks GA. (1992). Altitude acclimatization and energy metabolic adaptations in skeletal muscle during exercise. J Appl Physiol. 73(6): 2701-8.
Green H, MacDougall J, Tarnopolsky M, and Melissa NL. (1999). Downregulation of Na1-K1-ATPase pumps in skeletal muscle with training in normobaric hypoxia. J Appl Physiol. 86: 1745– 1748.
Guillemin K, Krasnow MA. (1997). The hypoxic response: huffing and HIFing. Cell. 89 (1): 9-12.
Gunga HC, Kirsch K, Rocker L, Behn C, Koralewski E, Davila EH, Estrada MI, Johannes B, Wittels P, Jelkmann W. (1999). Vascular endothelial growth factor in exercising humans under different environmental conditions. Eur J Appl Physiol Occup Physiol. 79 (6): 484-490.
Gustafsson T, Knutsson A, Puntschart A, Kaijser L, Nordqvist AC, Sundberg CJ, (2002). Jansson E. Increased expression of vascular endothelial growth factor in human skeletal muscle in response to short-term one-legged exercise training. Pflugers Arch. 444 (6): 752-759.
Gute D, Laughlin MH, and Amann JF. (1994). Regional changes in capillary supply in skeletal muscle of interval-sprint and lowintensity, endurance-trained rats. Microcirculation. 1: 183–193.
Hogenesch JB., Chan WK, Jackiw VH, Brown RC, GU YZ, Pray-Grant M, Perdew GH. Bradfield CA. (1997). Characterization of a subset of the basic-helix–loop–helix- PAS superfamily that interacts with components of the dioxin signaling pathway. J. biol. Chem. 272: 8581–8593.
Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P. (1990). Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 11 Suppl 1: S3-9.
Hoppeler H, Vogt M. (2001). Muscle tissue adaptations to hypoxia. The Journal of Experimental Biology. 204: 3133–3139.
Huang LE, Arany Z, Livingston DM, and Bunn HF. (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit. J Biol Chem. 271: 32253–32259.
Huang Q, Gao Y, Shi J, Liu F, Cao L, Sun B. (2000). Effects of hypoxia alone or exercise combined on capillarization of rat gastrocnemius muscle and its mechanism. Zhonghua Bing Li Xue Za Zhi. 29 (6): 439-442.
Hudlicka O, Brown M, and Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol Rev. 72: 369–417.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 292:5516 464-468.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim Av, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. (2001 ). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 292:5516 468-472.
Jeziorska M, Woolley DE.(1999). Neovascularization in early atherosclerotic lesions of human carotid arteries: its potential contribution to plaque development. Hum Pathol. 30 (8): 919-925.
Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. (1996). Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem Jul 26 271:30 17771-17778.
Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, and Poellinger L. (1998). Signal transduction in hypoxic cells: inducible nuclear localization and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1a. Embo J. 17: 6573–6586.
Kallio PJ, Wilson WJ, O’Brien S, Makino Y, and Poellinger L. (1999). Regulation of the hypoxia- inducible transcription factor 1 alpha by the ubiquitin-proteasome pathway. J Biol Chem. 274, 6519–6525.
Ladoux A, Frelin C. (1993 ). Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun. 195 (2): 1005-1010.
Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. (2002). Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 295: 5556 858-861.
Lash JM and Bohlen HG. (1992). Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training. J Appl Physiol. 72: 2052–2062.
Levine, D., & Stray-Gundersen, J. (1992). A practical approach to altitude training: Where to live and train for the optimal performance enhancement. Inter J Sports Med. 13: S209-S212.
Levine, D, & Stray-Gundersen,J. (1997). Living high-training low: Effect of moderate altitude acclimatization with low altitude on performance. J Appl Physiol. 83: 102-112.
Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M. (1996). VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol. 270(5 Pt 2): H1803-811.
Liu Y, Cox SR, Morita T, Kourembanas S. (1995). Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5' enhancer. Circ Res. 77 (3): 638-643.
Macdougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, Young P, Houston CS. (1991). Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 142 (3): 421-427.
Man'kovs'ka IM, Liabakh KH. (2003). Oxygen transport in skeletal muscles working with its maximum consumption during hypoxemia(abstract). Fiziol Zh. 49(3):75-79.
Melissa L, Macdougall JD, Tarnopolsky MA, Cipriano N, and Green HJ. (1997). Skeletal muscle adaptations to training under normobaric hypoxic versus normoxic conditions. Med Sci Sports Exerc. 29: 238–243.
Moravec M, Turek Z, Moravec J. (2002). Persistence of neoangiogenesis and cardiomyocyte divisions in right ventricular myocardium of rats born and raised in hypoxic conditions. Basic Res Cardiol. 97(2): 153-160.
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, Yamamoto H. (1995). Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia- induced proliferation of endothelial cells and pericytes. J Biol Chem. 270: 28316-28324.
Olfert, I. Mark, Ellen C. Breen, Odile Mathieu- Costello, and Peter D. Wagner. (2001). Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol. 91: 1176–1184.
Patan S, Tanda S, Roberge S, Jones RC, Jain RK, Munn LL. (2001a ). Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation. Circ Res. 89 (8): 732-739.
Patan S, Munn LL, Tanda S, Roberge S, Jain RK, Jones RC. (2001b ). Vascular morphogenesis and remodeling in a model of tissue repair: blood vessel formation and growth in the ovarian pedicle after ovariectomy. Circ Res. 89 (8): 723-731.
Patan S. (2004). Vasculogenesis and angiogenesis. Cancer Treat Res. 117: 3-32.
Rice AJ, Scroop GC, Gore CJ, Thornton AT, Chapman MA, Greville HW, Holmes MD, Scicchitano R.( 1999). Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake. Eur J Appl Physiol Occup Physiol. 79(4): 353-359.
Richardson, RS, Noyszewski EA, Kendrick KF, Leigh JS, and Wagner PD. (1995). Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J. Clin. Invest. 96: 1916–1926.
Richardson RS, Wagner H, Mudaliar SR, Saucedo E, Henry R, Wagner PD. ( 2000). Exercise adaptation attenuates VEGF gene expression in human skeletal muscle. Am J Physiol Heart Circ Physiol. 279 (2): H772-8.
Roach RC, Koskolou MD, Calbet JA, Saltin B.( 1999). Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans. Am J Physiol. 276(2 Pt 2): H438-45.
Ryan HE, Lo J, and Johnson RS. (1998). HIF-1a is required for solid tumor formation and embryonic vascularization. Embo J. 17: 3005–3015.
Sandner P, Wolf K, Bergmaier U, Gess B, Kurtz A.(1997a). Hypoxia and cobalt stimulate vascular endothelial growth factor receptor gene expression in rats. Pflugers Arch. 433 (6): 803-8.
Sandner P, Wolf K, Bergmaier U, Gess B, and Kurtz A. (1997b). Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro. Kidney Int. 51: 448–453.
Semenza GL, Wang GL. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 12: 5447-5454.
Semenza GL, Jiang B-H, Leung SW, Passantino R, Concordet J-P, Maire P, and Giallongo A. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 271, 32529–32537.
Shweiki D, Itin A, Soffer D, Keshet E. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 359(6398):843-5.
Sillau A and Banchero N. (1977). Effects of hypoxia on capillary density and fiber composition in rat skeletal muscle. Pflu¨ gers Arch. 370: 227–232.
Sosa Leon L, Hodgson DR, Evans DL, Ray SP, Carlson GP, Rose RJ. (2002). Hyperhydration prior to moderate-intensity exercise causes arterial hypoxaemia. Equine Vet J Suppl. 34: 425-9.
Suzuki J, Gao M, Batra S, and Koyama T. (1997). Effects of treadmill training on the arteriolar and venular portions of capillary in soleus muscle of young and middle-aged rats. Acta Physiol Scand. 159 (2): 113-121.
Tagarakis CV, Bloch W, Hartmann G, Hollmann W, Addicks K. ( 2000 ). Testosterone-propionate impairs the response of the cardiac capillary bed to exercise. Med Sci Sports Exerc. 32(5):946-953.
Takagi H, King GL, Robinson GS, Ferrara N, and Aiello LP. (1996). Hypoxic induction of VEGF is mediated by adenosine through A2 receptors and elevation of cAMP in retinal pericytes and endothelial cells. Invest Opthalmol Vis Sci. 37: 2165–2176.
Terrados N, Jansson E, Sylven C, and Kaijser L. (1990). Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? J Appl Physiol. 68: 2369–2372.
Tian, H., Mcknight, S. L. Russell, D. W. (1997). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11: 72–82.
Vogt, M., A. Puntschart, J. Geiser, C. Zuleger, R. Billeter, H. Hoppeler. (2001). Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. 91: 173–182.
Wang GL and Jiang BH. (1995a). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-Pas heterodimer regulated by cellular O2 tension. Genetics. 92: 5510–5514.
Wang GL, Jiang BH, Semenza GL. (1995b ). Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun. 212:2 550-556.
Wenger, R. H. and Gassmann, M. (1997). Oxygen(es) and the hypoxia-inducible factor-1. Biol. Chem. 378: 609–616.
White FC, Bloor CM, McKirnan MD, Carroll SM. (1998). Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart. J Appl Physiol. 85(3): 1160-1168.
Wood SM, Wiesener MS, Yeates KM et al. (1998). Selection and analysis of a mutant cell line defective in the hypoxia- inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of Hif- 1 alpha- dependent and -independent hypoxia-inducible gene expression. J Biol Chem. 273: 8360- 8368.
Zhou YD, Barnard M, Tian, Hli X, Ring, HZ, Francke, U, Shelton, J, Richardson, J, Russell, DW Mcknight, SL. (1997). Molecular characterization of two mammalian bHLHPAS domain proteins selectively expressed in the central nervous system. Proc natn Acad Sci. 94: 713–718.
Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM. (1996). An essential role for p300/CBP in the cellular response to hypoxia. Proc natn Acad Sci. 93: 12969-12973.
Asano M. (1998). Increase in serum vascular endothelial growth factor levels during altitude training. Acta Physiol Scand . 162(4): 455-459.
Banchero N. (1987). Cardiovascular responses to chronic hypoxia. Annu Rev Physiol. 49: 65-476.
Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. (1999). Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 13(1): 64-75.
Booth FW ,Thomason DB. (1991). Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev. 71: 541-585.
Breen EC, Johnson EC, Wagner H, Tseng HM, Sung LA, Wagner PD. (1996). Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol. 81: 355-361.
Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM. (1996). Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest. 97: 469-476.
Brown MD. (2003a). Exercise and coronary vascular remodelling in the healthy heart. Exp Physiol . 88: 645-658.
Brown MD. (2003b). Exercise and vascular remodeling. J Physiol. 547P SA18.
Brutsaert TD, Gavin TP, Fu Z, Breen EC, Tang K, Mathieu-Costello O, Wagner PD. (2002). Regional differences in expression of VEGF mRNA in rat gastrocnemius following 1 hr exercise or electrical stimulation. BMC physiology. 2: 8.
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394: 485-490.
Cerretelli P , Hoppeler H. (1996). Morphologic and metabolic responses to chronic hypoxia: the muscle system. In: Handbook of Physiology: Environmental Physiology. Bethesda, MD: Am. Physiol Soc., vol. II, chapt. 50: 1155-1181.
Claffey KP, Shih SC, Mullen A, Dziennis S, Cusick JL, Abrams KR, Lee SW, Detmar M. (1998). Identification of a human VPF/VEGF 39 untranslated region mediating hypoxiainduced mRNA stability. Mol Biol Cell. 9: 469-481.
Cosmas AC, Kernan K, Buck E, Fernhall B, Manfredi TG. (1997). Exercise and dietary cholesterol alter rat myocardial capillary ultrastructure. Eur J Appl Physiol Occup Physiol. 75: 62-67. Desplanches D, Hoppeler H, Linossier MT, Denis C, Claassen H, Dormios D, Lacour JR, Geyssant A. (1993). Effects of training in normoxia and normobaric hypoxia on human muscle ultrastructure. Pflu¨ gers Arch. 425: 263-267.
Desplanches DH, Hoppeler L, Tu¨ scher MH, Mayet H, Spielvogel G, Ferretti B, Kayser M, Leuenberger A, Gru¨ nenfelder R, Favier. (1996). Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia. J Appl Physiol. 81(5): 1946-1951.
Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y. (1999). Molecular mechanisms of transcription activation by HLF and HIF1a in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. 18: 1905-1914.
Esbjo¨ rnsson ME, Jansson CJ, Sundberg C, Sylven O,Eiken A, Nygren, Kaijser L. (1993). Muscle fibre types and enzyme activities after training with local leg ischaemia in man. Acta Physiol Scand. 148: 233-241.
Fong GH, Rossant J, Gerenstein M, Breitman M. (1995). Role of Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 376: 66-67.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16: 4604-4613.
Gavin TP, Spector DA, Wagner H, Breen EC, Wagner PD. (2000a). Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise. J Appl Physiol. 88: 1192-1198.
Gavin TP, Wagner H, Wagner PD. (2000b). VEGF receptor (FLT-1) mRNA response to acute exercise and nitric oxide synthase inhibition (Abstract). FASEB J. 14: A324.
Geiser J, Vogt M, Billeter R, Zuleger C, Belforti F, Hoppeler H. ( 2001). Training high--living low: changes of aerobic performance and muscle structure with training at simulated altitude. Int J Sports Med. 22(8): 579-585.
Gerber HP, Condorelli F, Park J, Ferrara N. (1997). Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. J Biol Chem. 272: 23659-23667.
Green H, MacDougall J, Tarnopolsky M, Melissa NL. (1999). Downregulation of Na1-K1- ATPase pumps in skeletal muscle with training in normobaric hypoxia. J Appl Physiol. 86: 1745- 1748.
Green HJ, Sutton JR, Wolfel EE, Reeves JT, Butterfield GE, Brooks GA. (1992). Altitude acclimatization and energy metabolic adaptations in skeletal muscle during exercise. J Appl Physiol. 73(6): 2701-2708.
Guillemin K, Krasnow MA. (1997). The hypoxic response: huffing and HIFing. Cell. 89(1): 9-12. Gustafsson T, Puntschart A, Kaijser L, Jansson E, Sundberg CJ. (1999). Exercise-induced expression of angiogenesisrelated transcription and growth factors in human skeletal muscle. Am J Physiol Heart Circ Physiol. 276: H679-685.
Gute D, Laughlin MH, Amann JF. (1994). Regional changes in capillary supply in skeletal muscle of interval-sprint and lowintensity, endurance-trained rats. Microcirculation. 1: 183-193.
Hogenesch JB, Chan WK, Jackiw VH, Brown RC, GU YZ, Pray-Grant M, Perdew G H, Bradfield CA. (1997). Characterization of a subset of the basic-helix–loop–helix- PAS superfamily that interacts with components of the dioxin signaling pathway. J biol Chem. 272: 8581-8593.
Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P. (1990). Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 1: S3-9.
Hoppeler H, Desplanches D. (1992). Muscle structural modifications in hypoxia. Int J Sports Med. 1: S166-S168.
Hoppeler H. (1999).Vascular growth in hypoxic skeletal muscle. Adv Exp Med Biol. 474: 277-286.
Huang LE, Arany Z, Livingston DM, Bunn HF. (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit. J Biol Chem. 271: 32253-32259.
Hudlicka O, Brown M, Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol Rev. 72: 369-417.
Iervolino AD, Trisciuoglio. (2002). Bcl-2 overexpression in human melanoma cells increases angiogenesis through VEGF mRNA stabilization and HIF-1-mediated transcriptional activity. The Faseb Journal : Official Publication of the Federation of American Societies For Experimental Biology. 16 (11): 1453-5.
Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. (1998). Signal transduction in hypoxic cells: inducible nuclear localization and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1a. EMBO J. 17: 6573-6586.
Kallio PJ, Wilson WJ, O’Brien S, Makino Y, Poellinger L. (1999). Regulation of the hypoxia-inducible transcription factor 1 alpha by the ubiquitin-proteasome pathway. J Biol Chem 274: 6519-6525.
Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura TD,_Acquisto F, Addeo R, Makuuchi M, Esumi H. ( 2000). Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood. 95: 1189-1197.
Lash JM, Bohlen HG. (1992). Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training. J Appl Physiol. 72: 2052-2062.
Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. ( 2001). HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 21:12 3995- 4004.
Levy AP, Levy NS, Wegner S, Goldberg MA. (1995). Transcriptional regulation of rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 270: 13333-13340.
Lewis AM, Mathieu-Costello O, Mc-Millan PJ, Gilbert RD.( 1999). Effects of long-term, high-altitude hypoxia on the capillarity of the ovine fetal heart. Am J Physiol. 277: H756-762.
Liu Y, Christou H, Morita T, Laughner E, Semenza GL, Kourembanas S.( 1998). Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5' enhancer. J Biol Chem. 273: 24 15257-15262.
Macdougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, Young P, Houston CS. (1991). Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 142(3): 421-427.
Martin C, Yu AY, Jiang BH, Davis L, Kimberly D, Hohimer AR, Semenza GL. (1998). Cardiac hypertrophy in chronically anemic fetal sheep: increased vascularization is associated with increased myocardial expression of vascular endothelial growth factor and hypoxia-inducible factor 1. Am J Obstet Gynecol. 178: 527-534.
Melissa L, Macdougall JD, Tarnopolsky MA, Cipriano N, Green HJ. (1997). Skeletal muscle adaptations to training under normobaric hypoxic versus normoxic conditions. Med Sci Sports Exerc. 29: 238-243.
Moravec M, Turek Z, Moravec J. (2002). Persistence of neoangiogenesis and cardiomyocyte divisions in right ventricular myocardium of rats born and raised in hypoxic conditions. Basic Res Cardiol 97(2): 153-160.
Neufer PD, Ordway GA, Williams RS. (1998). Transient regulation of c-fos, aB-crystallin, and hsp70 in muscle during recovery from contractile activity. Am J Physiol Cell Physiol. 274: C341-C346.
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, Yamamoto H. (1995). Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem. 270: 28316-28324.
Oelz O, Howald H, Di Prampero PE, Hoppeler H, Claassen H, Jenni R, Buhlmann A, Ferretti G, Bruckner JC, Veicsteinas A. (1986). Physiological profile of world-class high-altitude climbers. J Appl Physiol 60(5): 1734-1742.
Olfert IM, Breen EC, MathieuCostello O, Wagner PD. (2001a). Chronic hypoxia attenuates resting and exercise-induced VEGF, f lt-1, and f lk-1 mRNA levels in skeletal muscle. J Appl Physiol. 90: 1532-1538.
Olfert IM, Mark, Ellen C, Breen, Odile Mathieu, Costello, Peter D, Wagner. (2001b). Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol. 91: 1176-1184.
Osada M, Imaoka S, Sugimoto T, Hiroi T, Funae Y. (2002). NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1. J Biol Chem . 277 (26) : 23367-23373.
Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA. (1999). Hypoxia inducible factor 1a is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest Ophthalmol Vis Sci. 40: 182-189.
Pelster BA, S?nger M, Siegele, Schwerte T. ( 2003). Influence of swim training on cardiac activity, tissue capillarization, and mitochondrial density in muscle tissue of zebrafish larvae. Am J Physiol Regul Integr Comp Physiol. 85: R339-R347.
Pugh CW, O’Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. (1997). Activation of hypoxia-inducible factor-1; definition of regulatory domains within the a subunit. J Biol Chem. 272: 11205-11214.
Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. (1995). Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J. Clin. Invest. 96, 1916-1926.
Richardson RS, Wagner H, Mudaliar SRD, Henry R, Noyszewski EA, Wagner PD. (1999). Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise. Am J Physiol Heart Circ Physiol. 277: H2247-2252.
Richardson RS, Wagner H, Mudaliar SR, Saucedo E, Henry R, Wagner PD. (2000). Exercise adaptation attenuates VEGF gene expression in human skeletal muscle. Am J Physiol Heart Circ Physiol. 279(2): H772-778.
Ryan HE, Lo J, and Johnson RS. (1998). HIF-1a is required for solid tumor formation and embryonic vascularization. EMBO J. 17: 3005-3015.
Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV. (2002). The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol. 22(6): 1734-1741.
Sanchez, Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C. ( 2001). Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem. 276(42): 38527-38535.
Sandner P, Wolf K, Bergmaier U, Gess B, Kurtz A. (1997a). Hypoxia and cobalt stimulate vascular endothelial growth factor receptor gene expression in rats. Pflugers Arch. 433(6): 803-808.
Sandner P, Wolf K, Bergmaier U, Gess B, Kurtz A. (1997b). Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro. Kidney Int. 51: 448-453.
Semenza GL, Wang GL. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 12: 5447-5454.
Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 271: 32529-32537.
Semenza GL. ( 1998a). Hypoxia-inducible factor 1 and the molecular physiology of oxygen homeostasis. J Lab Clin Med. 131(3): 207-214.
Semenza GL. ( 1998b). Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet. 8: 588-594.
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. ( 1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 376: 65 35 62-3566.
Sillau A , Banchero N. (1977). Effects of hypoxia on capillary density and fiber composition in rat skeletal muscle. Pflu¨ gers Arch. 370: 227-232.
Suzuki J, Gao M, Batra S, Koyama T. (1997). Effects of treadmill training on the arteriolar and venular portions of capillary in soleus muscle of young and middle-aged rats. Acta Physiol Scand. 159 (2): 113-121.
Tagarakis CV, Bloch W, Hartmann G, Hollmann W, Addicks K. (2000). Testosterone-propionate impairs the response of the cardiac capillary bed to exercise. Med Sci Sports Exerc. 32(5): 946-953.
Takagi H, King GL, Robinson GS, Ferrara N, Aiello LP. (1996). Hypoxic induction of VEGF is mediated by adenosine through A2 receptors and elevation of cAMP in retinal pericytes and endothelial cells. Invest Opthalmol Vis Sci. 37: 2165-2176.
Terrados N, Jansson E, Sylven C, Kaijser L. (1990). Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? .J Appl Physiol. 68: 2369-2372. Tian H, Mcknight SL, Russell DW. (1997). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes. 11: 72-82.
Treins C, GiorgettiPeraldi S, Murdaca J, Semenza GL, VanObberghen E.(2002). Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem . 277: 31 27975-27981.
Tuder RM, Flook BE, Voelkel NF. (1995). Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or chronic hypoxia. J Clin Invest. 95: 1798-1807.
Vogt MA, Puntschart J, Geiser C, Zuleger R, Billeter H, Hoppeler. (2001). Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol. 91: 173-182.
Wang GL, Jiang BH. (1995a). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-Pas heterodimer regulated by cellular O2 tension. Genetics. 92: 5510-5514.
Wang GL, Jiang BH, Semenza GL. (1995b). Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun. 212: 2550-2 556.
Wenger RH, Gassmann M. (1997). Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem. 378: 609-616.
White FC, Bloor CM, McKirnan MD, Carroll SM. (1998). Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart. J Appl Physiol. 85(3): 1160-1168.
Wood SM, Wiesener MS, Yeates KM. (1998). Selection and analysis of a mutant cell line defective in the hypoxia- inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of Hif- 1alpha-dependent and -independent hypoxia-inducible gene expression. J Biol hem. 273: 8360-8368.
Yin Z, Haynie J, Yang X, Han B, Kiatchoosakun S, Restivo J, Yuan S, Prabhakar NR, Herrup K, Conlon RA, Hoit BD, Watanabe M, Yang YC. (2002). The essential role of Cited2, a negative regulator for HIF-1α, in heart development and neurulation. Proc Natl Acad Sci. 99(16): 10488-10493.
Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, Shelton J, Richardson J, Russell DW, Mcknight SL. (1997). Molecular characterization of two mammalian bHLHPAS domain proteins selectively expressed in the central nervous system. Proc natn Acad Sci. 94: 713-718.