妊娠期慢性缺氧对子代大鼠血压的影响及相关机制研究
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摘要
目的:本课题通过对妊娠期缺氧子代大鼠的研究,探讨妊娠不同时期的慢性缺氧对雌雄子代血压的影响,并初步探讨其可能机理。
方法:SD大鼠孕鼠25只,随机均分为4个缺氧组(H组)和一个正常对照组(C组)。其中H组均分为孕全期、早、中、晚期缺氧(H1,H2,H3 ,H4组),O2浓度10±1% ,每天定时缺氧3小时,C组模拟放入缺氧箱中,O2浓度21%。出生子代大鼠分别于1天龄、1月龄、3月龄、6月龄每组随机各取雌雄子鼠5只。分别选用无创血压仪检测子鼠血压及心率;测定子鼠体重,称量主要脏器重量;HE法观测心脏、肾脏病理变化;Masson三色特染法分析主动脉、颈动脉及股动脉的肌纤维及胶原纤维病理变化;免疫组织化学法检测心脏eNOS、iNOS蛋白表达,肾脏InR蛋白表达;ELISA法检测血清ET-1蛋白质表达;荧光定量PCR法检测心肌ET-1、ECE-1、肾脏IRS-1、IRS-2 mRNA含量。
结果: 1、缺氧组子代3月龄即表现出血压升高,6月龄升高更加明显,各缺氧组均比对照组血压升高(P<0.05),以妊娠中期缺氧的雄性子代升高最为明显(136.80±2.18&110.20±2.18)各组心率无明显差别(P>0.05);
2、缺氧组出现低出生体重、主要脏器不成比例生长及产后的“追赶生长现象”;3、缺氧组较对照组主动脉、颈动脉及股动脉弹性血管的形态学发生改变,血管胶原纤维增多、肌纤维部分萎缩、纤维素沉着等;4、缺氧组较对照组局部eNOS、iNOS、血清及局部ET-1、ECE-1、InR、IRS-1、IRS-2表达改变(均P<0.05)。
结论:妊娠期慢性缺氧可致成年子代大鼠血压升高,低出生体重及各脏器不成比例生长,程序化调控一氧化氮和内皮素这两大相拮抗体系及干扰胰岛素信号传递过程,胰岛素调节受损,共同参与血管内皮功能受损过程,血管形态学发生变化,心血管系统的舒缩功能紊乱,以雄性子代妊娠中期缺氧血压升高最为明显,提示妊娠期慢性缺氧在子代成年后高血压的发生中起着重要作用。
Objective:To explore the effects of Prenatal chronic hypoxia on the systemic blood pressure in the offspring rats,and investigate its potential mechanism.
Methods:25 pregnant SD rats were divided randomly into 5 groups:4 Prenatal chronic hypoxia groups(H group)and a control group (C group).H groups were divided into whole,early, middle and late Prenatal hypoxia group(H1, H2, H3, H4 group) and,Prenatal chronic hypoxia group were put into hypoxia box 3 hours per day(10±1% O2) and the control group(21% O2). 5 male and 5 female offspring of each group were studied when the descendant rats were 1 day,1 month,3 month and 5 month old. We monitored their blood pressure and heart rate by indirect measurement and measured their weight of organs and body weight of offspring;HE was used to observe pathological changes of heart and kidney;Masson trichrome special dyeing was used to observed the pathological changes of the muscle fibers and collagen fibers in aorta,carotid and femoral arteries; immunohistochemistry was used to detecte the protein expression of eNOS and iNOS in heart and Insulin receptor in kidney;ELISA was used to measure the plasma ET-1 expression, real-time quantitative PCR was used to observe the mRNA expression of myocardial ET-1, ECE-1 and IRS-1, IRS-2 in kidney.
Results: 1,Tthe blood pressure of hypoxia group offspring is increased at 3 months old, it was higher than the control group significantly at 6 months old (P <0.05), the medium-term hypoxia male offspring is increased most than the contol group(136.80±2.18 & 110.20±2.18),the heart rate was no significant difference in each group (P> 0.05); 2, Prenatal chronic hypoxia result in low birth weight , disproportionate growth of major offspring organs and postnatal "catch-up growth phenomenon"; 3,Prenatal chronic hypoxia lead to orphological changes of aorta, carotid and femoral arteries—vascular collagen fibers increased, some muscle fiber atrophy, fibrin deposition; 4, Prenatal chronic hypoxia changes the expression of local eNOS, iNOS, serum and local ET-1, ECE-1, InR , IRS-1, IRS-2 (all P <0.05).
Conclusion: The chronic hypoxia during pregnancy can elevate blood pressure of adult offspring ,result in low birth weight , disproportionate growth of major offspring organs and postnatal "catch-up growth phenomenon", regulate procedurely NO/ET ,interfere the processe of insulin signaling, impaire insulin regulation,participate in the process of endothelial and the cardiovascular system dysfunction, change vascular morphological.All these changes are most obviously observed in the medium-term hypoxia male offspring rats,which indicates chronic hypoxia during pregnancy may play an important role in offspring adult system hypertension.
方法:SD大鼠孕鼠25只,随机均分为4个缺氧组(H组)和一个正常对照组(C组)。其中H组均分为孕全期、早、中、晚期缺氧(H1,H2,H3 ,H4组),O2浓度10±1% ,每天定时缺氧3小时,C组模拟放入缺氧箱中,O2浓度21%。出生子代大鼠分别于1天龄、1月龄、3月龄、6月龄每组随机各取雌雄子鼠5只。分别选用无创血压仪检测子鼠血压及心率;测定子鼠体重,称量主要脏器重量;HE法观测心脏、肾脏病理变化;Masson三色特染法分析主动脉、颈动脉及股动脉的肌纤维及胶原纤维病理变化;免疫组织化学法检测心脏eNOS、iNOS蛋白表达,肾脏InR蛋白表达;ELISA法检测血清ET-1蛋白质表达;荧光定量PCR法检测心肌ET-1、ECE-1、肾脏IRS-1、IRS-2 mRNA含量。
结果: 1、缺氧组子代3月龄即表现出血压升高,6月龄升高更加明显,各缺氧组均比对照组血压升高(P<0.05),以妊娠中期缺氧的雄性子代升高最为明显(136.80±2.18&110.20±2.18)各组心率无明显差别(P>0.05);
2、缺氧组出现低出生体重、主要脏器不成比例生长及产后的“追赶生长现象”;3、缺氧组较对照组主动脉、颈动脉及股动脉弹性血管的形态学发生改变,血管胶原纤维增多、肌纤维部分萎缩、纤维素沉着等;4、缺氧组较对照组局部eNOS、iNOS、血清及局部ET-1、ECE-1、InR、IRS-1、IRS-2表达改变(均P<0.05)。
结论:妊娠期慢性缺氧可致成年子代大鼠血压升高,低出生体重及各脏器不成比例生长,程序化调控一氧化氮和内皮素这两大相拮抗体系及干扰胰岛素信号传递过程,胰岛素调节受损,共同参与血管内皮功能受损过程,血管形态学发生变化,心血管系统的舒缩功能紊乱,以雄性子代妊娠中期缺氧血压升高最为明显,提示妊娠期慢性缺氧在子代成年后高血压的发生中起着重要作用。
Objective:To explore the effects of Prenatal chronic hypoxia on the systemic blood pressure in the offspring rats,and investigate its potential mechanism.
Methods:25 pregnant SD rats were divided randomly into 5 groups:4 Prenatal chronic hypoxia groups(H group)and a control group (C group).H groups were divided into whole,early, middle and late Prenatal hypoxia group(H1, H2, H3, H4 group) and,Prenatal chronic hypoxia group were put into hypoxia box 3 hours per day(10±1% O2) and the control group(21% O2). 5 male and 5 female offspring of each group were studied when the descendant rats were 1 day,1 month,3 month and 5 month old. We monitored their blood pressure and heart rate by indirect measurement and measured their weight of organs and body weight of offspring;HE was used to observe pathological changes of heart and kidney;Masson trichrome special dyeing was used to observed the pathological changes of the muscle fibers and collagen fibers in aorta,carotid and femoral arteries; immunohistochemistry was used to detecte the protein expression of eNOS and iNOS in heart and Insulin receptor in kidney;ELISA was used to measure the plasma ET-1 expression, real-time quantitative PCR was used to observe the mRNA expression of myocardial ET-1, ECE-1 and IRS-1, IRS-2 in kidney.
Results: 1,Tthe blood pressure of hypoxia group offspring is increased at 3 months old, it was higher than the control group significantly at 6 months old (P <0.05), the medium-term hypoxia male offspring is increased most than the contol group(136.80±2.18 & 110.20±2.18),the heart rate was no significant difference in each group (P> 0.05); 2, Prenatal chronic hypoxia result in low birth weight , disproportionate growth of major offspring organs and postnatal "catch-up growth phenomenon"; 3,Prenatal chronic hypoxia lead to orphological changes of aorta, carotid and femoral arteries—vascular collagen fibers increased, some muscle fiber atrophy, fibrin deposition; 4, Prenatal chronic hypoxia changes the expression of local eNOS, iNOS, serum and local ET-1, ECE-1, InR , IRS-1, IRS-2 (all P <0.05).
Conclusion: The chronic hypoxia during pregnancy can elevate blood pressure of adult offspring ,result in low birth weight , disproportionate growth of major offspring organs and postnatal "catch-up growth phenomenon", regulate procedurely NO/ET ,interfere the processe of insulin signaling, impaire insulin regulation,participate in the process of endothelial and the cardiovascular system dysfunction, change vascular morphological.All these changes are most obviously observed in the medium-term hypoxia male offspring rats,which indicates chronic hypoxia during pregnancy may play an important role in offspring adult system hypertension.
引文
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[1]Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective[J]. Pediatr Res,2004,56(3):311-7.
[2]Gluckman PD, Hanson MA, Cooper C,et al.Effect of in utero and early-life conditions on adult health and disease[J].N Engl J Med,2008,359(1):61-73.
[3]Keyes LE, Armaza JP, et al. Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia[J]. Pediatr Res,2003,54(1):20-5.
[4]Godfrey KM, Barker DJ. Fetal programming and adult health[J].Public Health Nutr,2001,4(2B):611-24.
[5]Peyronnet J,Dalmaz Y, Ehrstr?m M,et al. Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats[J]. Pflugers Arch,2002,443(5-6):858–65.
[6]Zandi-Nejad K, Luyckx VA, Brenner BM.Adult hypertension and kidney disease: the role of fetal programming[J].Hypertension,2006,47(3):502-8.
[7]Bae S, Xiao Y, Li G, Casiano CA, Zhang L .Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart[J]. Am J Physiol Heart Circ Physiol,2003,285(3): H983-90..
[8]Rueda-Clausen CF, Morton JS, Davidge ST. Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood[J].Cardiovasc Res, 2009,81(4):713-22.
[9]Xu Y, Williams SJ, O'Brien D, et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring.FASEB J,2006,20(8):1251-3.
[10]Fuller KE.Low birth-weight infants: the continuing ethnic disparity and the interaction of biology and environment[J].Ethn Dis,2000,10(3):432–45.
[11]Bergvall N,lliadou A,Johansson S,et al. Genetic and shared environmental factors do not confound the association between birth weight and hypertension: a study among Swedish twins [J].Circulation,2007,115(23):2931-8.
[12]Frasch MG, Müller T, Wicher C,et a1.Fetal body weight and the development of the control of the cardiovascular system in fetal sheep[J].J Physiol,2007,579(Pt3):893-907.
[13]Lackland DT,Egan BM,Syddall HE,et al .Associations between birth weishtand antihypertensive medication in black and white medical recipients[J].Hypertension,2002,39(1):179-83.
[14]林惠通,吕国荣,王振华,李伯义.慢性宫内缺氧增强子代兔成年期腹主动脉C反应蛋白和单核细胞趋化因子1的表达[J].中华高血压杂志,2009 ,17(4): 328-333.
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[22]周静,王金文,李晓云等.一氧化氮通路可能部分介导salusin-β中枢降血压作用[J].中华高血压杂志,2010,18(5): 434-438 .
[23]Turley JE, Nelin LD, et al.Exhaled NO is reduced at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets[J]. Am J Physiol Lung Cell Mol Physiol,2003,284(3):489–500.
[24]Castro MG,Rodríguez Pascual F,et al.Screening of the endothelin1 gene (EDN1)in a cohort of patients with essential left ventricular hypertrophy[J].Ann Hum Genet,2007,71(Pt5):601-10.
[25]Dendorfer A ,Dominiak P ,Schunkert H .ACE Inhibitors and angiotensin II receptor antagonists[J] .Handb Exp Pharmacol ,2005,(170):407-42.
[26]宗文纳,卢新政,陈秀梅,等.血浆血管紧张素Ⅱ1型受体及其抗体与血压的关系[J].中华高血压杂志,2010,18(5):429-433.
[27]Schultz Jel J, Witt SA, Glascock BJ, et al. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II [J].J Clin Invest,2002,109(6):787-96.
[28]Sodhi CP, Kanwar YS, Sahai A.Hypoxia and high glucose upregulate AT1 receptor expression and potentiate ANG II-induced proliferation in VSM cells[J].Am J Physiol Heart Circ Physiol, 2003,284(3):H846-52.
[29]Fowden AL,Giussani DA,Forhead AJ.Endocrine and metabolic programming during intrauterine development[J].Early Hum Dev,2005,81(9):723-34.
[30]Mardilovich K,Shaw LM.Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion[J]. Cancer Res,2009,69(23):8894-901.
[31]林惠通,吕国荣,王振华,等.慢性宫内缺氧对子代兔成年期血管内皮舒张功能及内膜病理改变的影响[J].中国动脉硬化杂志,2009,17(2):93-96.
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[1]Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective[J]. Pediatr Res,2004,56(3):311-7.
[2]Gluckman PD, Hanson MA, Cooper C,et al.Effect of in utero and early-life conditions on adult health and disease[J].N Engl J Med,2008,359(1):61-73.
[3]Keyes LE, Armaza JP, et al. Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia[J]. Pediatr Res,2003,54(1):20-5.
[4]Godfrey KM, Barker DJ. Fetal programming and adult health[J].Public Health Nutr,2001,4(2B):611-24.
[5]Peyronnet J,Dalmaz Y, Ehrstr?m M,et al. Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats[J]. Pflugers Arch,2002,443(5-6):858–65.
[6]Zandi-Nejad K, Luyckx VA, Brenner BM.Adult hypertension and kidney disease: the role of fetal programming[J].Hypertension,2006,47(3):502-8.
[7]Bae S, Xiao Y, Li G, Casiano CA, Zhang L .Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart[J]. Am J Physiol Heart Circ Physiol,2003,285(3): H983-90..
[8]Rueda-Clausen CF, Morton JS, Davidge ST. Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood[J].Cardiovasc Res, 2009,81(4):713-22.
[9]Xu Y, Williams SJ, O'Brien D, et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring.FASEB J,2006,20(8):1251-3.
[10]Fuller KE.Low birth-weight infants: the continuing ethnic disparity and the interaction of biology and environment[J].Ethn Dis,2000,10(3):432–45.
[11]Bergvall N,lliadou A,Johansson S,et al. Genetic and shared environmental factors do not confound the association between birth weight and hypertension: a study among Swedish twins [J].Circulation,2007,115(23):2931-8.
[12]Frasch MG, Müller T, Wicher C,et a1.Fetal body weight and the development of the control of the cardiovascular system in fetal sheep[J].J Physiol,2007,579(Pt3):893-907.
[13]Lackland DT,Egan BM,Syddall HE,et al .Associations between birth weishtand antihypertensive medication in black and white medical recipients[J].Hypertension,2002,39(1):179-83.
[14]林惠通,吕国荣,王振华,李伯义.慢性宫内缺氧增强子代兔成年期腹主动脉C反应蛋白和单核细胞趋化因子1的表达[J].中华高血压杂志,2009 ,17(4): 328-333.
[15]杨景阳,黄子扬.宫内不良环境与慢性成年疾病关系的研究进展[J].心血管病学进展,2008 ,29(1):103-106.
[16]Zandi-Nejad K, Luyckx VA, Brenner BM. Adult Hypertension and Kidney Disease:the role of fetal programming[J]. Hypertension,2006,47(3):502-8.
[17]Ojeda NB, Grigore D, Alexander BT. Intrauterine growth restriction: fetal programming of hypertension and kidney disease.Adv Chronic Kidney Dis, 2008 ,15(2): 101–6.
[18]Wang Z, Huang Z, Lu G, Lin L, Ferrari M.Hypoxia during pregnancy in rats leads to early morphological changes of atherosclerosis in adult offspring[J]. Am J Physiol Heart Circ Physiol,2009,296(5):H1321-8.
[19]Brunner F,Maier R, et a1.Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase[J].Cardiovasc Res,2003,57(1):55-62.
[20]田心,王蓓,王长海,马静.以自发性高血压大鼠为模型对高血压发病机制的研究[J].Central China Medical Journal,2009,33(2):112-114.
[21]Wang CH, Li SH, Weisel RD, et al. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle [ J ] . Circulation,2003,107(13):1783-90.
[22]周静,王金文,李晓云等.一氧化氮通路可能部分介导salusin-β中枢降血压作用[J].中华高血压杂志,2010,18(5): 434-438 .
[23]Turley JE, Nelin LD, et al.Exhaled NO is reduced at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets[J]. Am J Physiol Lung Cell Mol Physiol,2003,284(3):489–500.
[24]Castro MG,Rodríguez Pascual F,et al.Screening of the endothelin1 gene (EDN1)in a cohort of patients with essential left ventricular hypertrophy[J].Ann Hum Genet,2007,71(Pt5):601-10.
[25]Dendorfer A ,Dominiak P ,Schunkert H .ACE Inhibitors and angiotensin II receptor antagonists[J] .Handb Exp Pharmacol ,2005,(170):407-42.
[26]宗文纳,卢新政,陈秀梅,等.血浆血管紧张素Ⅱ1型受体及其抗体与血压的关系[J].中华高血压杂志,2010,18(5):429-433.
[27]Schultz Jel J, Witt SA, Glascock BJ, et al. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II [J].J Clin Invest,2002,109(6):787-96.
[28]Sodhi CP, Kanwar YS, Sahai A.Hypoxia and high glucose upregulate AT1 receptor expression and potentiate ANG II-induced proliferation in VSM cells[J].Am J Physiol Heart Circ Physiol, 2003,284(3):H846-52.
[29]Fowden AL,Giussani DA,Forhead AJ.Endocrine and metabolic programming during intrauterine development[J].Early Hum Dev,2005,81(9):723-34.
[30]Mardilovich K,Shaw LM.Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion[J]. Cancer Res,2009,69(23):8894-901.
[31]林惠通,吕国荣,王振华,等.慢性宫内缺氧对子代兔成年期血管内皮舒张功能及内膜病理改变的影响[J].中国动脉硬化杂志,2009,17(2):93-96.