血流切应力变化对大鼠颈总动脉重建的影响及其机制
|
摘要
正常的血流切应力对于维持血管正常功能包括抗血栓形成、屏障功能和血管本身的动态平衡都是至关重要的。血流切应力变化将导致血管重建(remodeling),而病理性的血管重建是动脉粥样硬化、高血压和血管再狭窄等病变共同的病理基础。了解切应力变化对血管重建的影响及其机制,对探讨心血管疾病的发病机制、诊断与治疗有重要的理论和实际意义。
本文采用了结扎一侧颈总动脉部分分支,造成两侧颈总动脉的血流切应力显著改变的大鼠模型,研究血流切应力变化对颈总动脉重建的影响并初步探讨其机制。以不结扎动脉分支的假手术动物作为对照组。采用光镜和透射电镜观察动脉显微组织结构、几何形态学和超微结构的变化;观测动脉零应力状态下张开角的变化;应用TUNNEL法观察了血管平滑肌细胞(VSMC)凋亡;用激光共聚焦显微镜观测动脉内弹力膜(IEL)重建;并用大分子示踪剂辣根过氧化物酶(HRP)示踪法研究了IEL通透性的变化;用免疫组化和免疫印迹法检测了动脉calponin, fibronectin, p-Akt, p21等分子表达;用明胶酶谱法研究了基质金属蛋白酶(MMPs)活性,并在应用了MMPs的抑制剂“强力霉素”对血管重建进行干预后,再观察calponin, p-Akt, p21, MMPs表达的变化。
结果显示:①结扎大鼠左颈总动脉(LCA)的远侧部分分支,造成同一动物LCA的低平均切应力状态,对侧右颈总动脉(RCA)高平均切应力状态。在切应力显著降低7天后,LCA管径减小,壁厚内径比增加,张开角减小,VSMC凋亡和去分化增加,内皮下层增厚;而RCA的管径和壁厚内径比未见明显变化,但VSMC的凋亡和去分化也显著增加;②切应力的降低导致LCA的IEL窗减小,通透性改变,大分子示踪剂在IEL下层的显著聚积,并伴有fibronectin表达的增加;明显区别于高切应力RCA的变化;③切应力的显著变化导致血管内MMPs的活性增加,并伴有Akt / p21信号通路的活化;应用MMPs的抑制剂“强力霉素”可以显著抑制MMPs的活性,同时也在一定程度上抑制了切应力诱导的Akt / p21信号通路的活化及VSMC的去分化。
上述结果表明,在血流切应力降低的较早阶段即出现动脉壁的结构性重建,其中以IEL的重建最为显著,并可导致大分子物质在动脉壁内的异常聚积。血流切应力变化增加了MMPs的活性,而MMPs的抑制剂可能在多个环节上拮抗切应力变化所诱导的血管重建,以维持血管结构和功能的稳定。
Physiological flow shear stress plays a central role in anti-thrombus, maintaining barrier function and homestasis of blood vessel. The alterated flow shear stress would induce vessel remodeling, which was the common pathological foundation of vascular diseases such as atherosclerosis, hypertension and restenosis. Therefore, it is very important to eluciate the underlying mechanisms of the vascular remodeling induced by flow shear stress alterations for the prevention, diagnosis and treatment of cardiovascular diseases.
In present study, the ligation of partial distal branches of the left common carotid (LCA) was performed, which resulted in different changes of flow shear stress in both carotids of the same rat. The sham-operation animals without arterial ligation were as a control group. The effects of shear stress alteration on remodeling of carotid arteries and underlying mechanisms were inspected. The morphometry, histology, and ultrastructures of the vessels were examined by both light microscopy and transmission electron microscopy. The changes of vascular opening angle at zero-stress state were detected. Apoptotic cells of the vascular wall were examined by TdT-mediated dUTP-biotin nick end labeling (TUNNEL) staining. The vascular internal elastic lamina (IEL) was insighted with horseradish peroxidase (HRP), a large molecular tracer, by laser confocal scanning microscopy. The expressions of calponin, fibronectin, p-Akt and p21 in the vascular wall were examined by immunohistochemistry and Western blotting. The activity of matrix metalloproteinases (MMPs) in the vascular wall was revealed by gelatin zymography.
Our results revealed that: (1) The ligation of partial distal branches of LCA induced low shear stress of LCA and high shear stress of the contralateral right carotid arteries (RCA). At 7th day of post-operation both the inner diameter and opening angle of LCA were decreased, while the ratio of wall thickness to inner diameter was increased. RCA did not show such changes. The apoptic and dedifferentiated vascular smooth muscle cells were increased due to changes of shear stress. The thickness of sub-endothelial layer was increased in LCA significantly. (2) Low shear stress induced the decrease of IEL fenestrae, which resulted in abnormal molecular accumulation in the interstitial space underlying IEL with augmented expression of fibronectin, significantly different from RCA. (3) Changes of shear stress increased the MMPs activities and p-Akt expressions, while reduced expressions of p21 and calponin in vessels, which was reversed by Doxycycline, an inhibitor of MMPs.
These results revealed that low shear stress induced structural changes of artery, especially IEL remodeling, and resulted in macromolecular accumulation in the arterial wall at more early in course of the alternation of shear stress. The alteration of shear stress induced MMPs activities in the vascular wall. Otherwise, the inhibitor of MMPs might benefit to the vascular remodeling induced by the alternation of shear stress.
本文采用了结扎一侧颈总动脉部分分支,造成两侧颈总动脉的血流切应力显著改变的大鼠模型,研究血流切应力变化对颈总动脉重建的影响并初步探讨其机制。以不结扎动脉分支的假手术动物作为对照组。采用光镜和透射电镜观察动脉显微组织结构、几何形态学和超微结构的变化;观测动脉零应力状态下张开角的变化;应用TUNNEL法观察了血管平滑肌细胞(VSMC)凋亡;用激光共聚焦显微镜观测动脉内弹力膜(IEL)重建;并用大分子示踪剂辣根过氧化物酶(HRP)示踪法研究了IEL通透性的变化;用免疫组化和免疫印迹法检测了动脉calponin, fibronectin, p-Akt, p21等分子表达;用明胶酶谱法研究了基质金属蛋白酶(MMPs)活性,并在应用了MMPs的抑制剂“强力霉素”对血管重建进行干预后,再观察calponin, p-Akt, p21, MMPs表达的变化。
结果显示:①结扎大鼠左颈总动脉(LCA)的远侧部分分支,造成同一动物LCA的低平均切应力状态,对侧右颈总动脉(RCA)高平均切应力状态。在切应力显著降低7天后,LCA管径减小,壁厚内径比增加,张开角减小,VSMC凋亡和去分化增加,内皮下层增厚;而RCA的管径和壁厚内径比未见明显变化,但VSMC的凋亡和去分化也显著增加;②切应力的降低导致LCA的IEL窗减小,通透性改变,大分子示踪剂在IEL下层的显著聚积,并伴有fibronectin表达的增加;明显区别于高切应力RCA的变化;③切应力的显著变化导致血管内MMPs的活性增加,并伴有Akt / p21信号通路的活化;应用MMPs的抑制剂“强力霉素”可以显著抑制MMPs的活性,同时也在一定程度上抑制了切应力诱导的Akt / p21信号通路的活化及VSMC的去分化。
上述结果表明,在血流切应力降低的较早阶段即出现动脉壁的结构性重建,其中以IEL的重建最为显著,并可导致大分子物质在动脉壁内的异常聚积。血流切应力变化增加了MMPs的活性,而MMPs的抑制剂可能在多个环节上拮抗切应力变化所诱导的血管重建,以维持血管结构和功能的稳定。
Physiological flow shear stress plays a central role in anti-thrombus, maintaining barrier function and homestasis of blood vessel. The alterated flow shear stress would induce vessel remodeling, which was the common pathological foundation of vascular diseases such as atherosclerosis, hypertension and restenosis. Therefore, it is very important to eluciate the underlying mechanisms of the vascular remodeling induced by flow shear stress alterations for the prevention, diagnosis and treatment of cardiovascular diseases.
In present study, the ligation of partial distal branches of the left common carotid (LCA) was performed, which resulted in different changes of flow shear stress in both carotids of the same rat. The sham-operation animals without arterial ligation were as a control group. The effects of shear stress alteration on remodeling of carotid arteries and underlying mechanisms were inspected. The morphometry, histology, and ultrastructures of the vessels were examined by both light microscopy and transmission electron microscopy. The changes of vascular opening angle at zero-stress state were detected. Apoptotic cells of the vascular wall were examined by TdT-mediated dUTP-biotin nick end labeling (TUNNEL) staining. The vascular internal elastic lamina (IEL) was insighted with horseradish peroxidase (HRP), a large molecular tracer, by laser confocal scanning microscopy. The expressions of calponin, fibronectin, p-Akt and p21 in the vascular wall were examined by immunohistochemistry and Western blotting. The activity of matrix metalloproteinases (MMPs) in the vascular wall was revealed by gelatin zymography.
Our results revealed that: (1) The ligation of partial distal branches of LCA induced low shear stress of LCA and high shear stress of the contralateral right carotid arteries (RCA). At 7th day of post-operation both the inner diameter and opening angle of LCA were decreased, while the ratio of wall thickness to inner diameter was increased. RCA did not show such changes. The apoptic and dedifferentiated vascular smooth muscle cells were increased due to changes of shear stress. The thickness of sub-endothelial layer was increased in LCA significantly. (2) Low shear stress induced the decrease of IEL fenestrae, which resulted in abnormal molecular accumulation in the interstitial space underlying IEL with augmented expression of fibronectin, significantly different from RCA. (3) Changes of shear stress increased the MMPs activities and p-Akt expressions, while reduced expressions of p21 and calponin in vessels, which was reversed by Doxycycline, an inhibitor of MMPs.
These results revealed that low shear stress induced structural changes of artery, especially IEL remodeling, and resulted in macromolecular accumulation in the arterial wall at more early in course of the alternation of shear stress. The alteration of shear stress induced MMPs activities in the vascular wall. Otherwise, the inhibitor of MMPs might benefit to the vascular remodeling induced by the alternation of shear stress.
引文
1. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med, 1999, 340(2):115-26.
2. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol, 2004, 24(1):12-22.
3. Wissler RW, Strong JP. Risk factors and progression of atherosclerosis in youth. PDAY Research Group. Pathological Determinants of Atherosclerosis in Youth. Am J Pathol, 1998, 153(4):1023-33.
4. Wyttenbach R, Gallino A, Alerci M, Mahler F, Cozzi L, Di Valentino M, Badimon JJ, Fuster V, Corti R. Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery by noninvasive magnetic resonance imaging. Circulation, 2004, 110(9):1156-61.
5. Friedman MH, Bargeron CB, Deters OJ, Hutchins GM, Mark FF. Correlation between wall shear and intimal thickness at a coronary artery branch. Atherosclerosis, 1987, 68(1-2):27-33.
6. Ku DN, Giddens DP, Zarins CK, Glagov S. Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis, 1985, 5(3):293-302.
7. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci, 2000, 902:230-9.
8. Davies PF. Spatial hemodynamics, the endothelium, and focal atherogenesis: a cell cycle link? Circ Res, 2000, 86(2):114-6.
9. Chien S, Li S, Shyy YJ. Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension, 1998, 31(1 Pt 2):162-9.
10. Berk BC, Abe JI, Min W, Surapisitchat J, Yan C. Endothelial atheroprotective and anti-inflammatory mechanisms. Ann N Y Acad Sci, 2001, 947:93-109.
11. Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol, 1980, 239:H14-H21.
12. Langille BL, O'Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science, 1986, 231: 405-7.
13. Ji JY, Jing H, Diamond SL. Shear stress causes nuclear localization of endothelial glucocorticoid receptor and expression from the GRE promoter. Circ Res, 2003, 92(3):279-85.
14. Endemann G, Abe Y, Bryant CM, Feng Y, Smith CW, Liu DY. Novel anti-inflammatory compounds induce shedding of L-selectin and block primary capture of neutrophils under flow conditions. J Immunol, 1997, 158(10):4879-85.
15. Guzman LA, Mick MJ, Arnold AM, Forudi F, Whitlow PL. Role of intimal hyperplasia and arterial remodeling after balloon angioplasty: an experimental study in the atherosclerotic rabbit model. Arterioscler Thromb Vasc Biol, 1996, 16:479-487.
16. Sho E, Nanjo H, Sho M, Kobayashi M, Komatsu M, Kawamura K, Xu C, Zarins CK, Masuda H. Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress. J Vasc Surg. 2004, 39:601-12.
17. Wolf C, Cai WJ, Vosschulte R, Koltai S, Mousavipour D, Scholz D, Afsah-Hedjri A, Schaper W, Schaper J. Vascular remodeling and altered protein expression during growth of coronary collateral arteries. J Mol Cell Cardiol, 1998, 30: 2291–2305.
18. Tulis DA, Unthank JL, Prewitt RL. Flow-induced arterial remodeling in rat mesenteric vasculature. Am J Physiol, 1998, 274: H874–H882.
19. Groves J, Wang Z, Newman WH. Two distinct phenotypes of rat vascularsmooth muscle cells: growth rate and Production of tumor necrosis factor-alpha. Am Surg, 2005, 71(7):546-50.
20. Su BY, Shontz KM, Flavahan NA, Nowicki PT. The effect of phenotype on mechanical stretch-induced vascular smooth muscle cell apoptosis. J Vasc Res, 2006, 43(3):229-37.
21. Fung YC. Biodynamics: Circulation. New York: Springer Verlag, 1984.54-63.
22. Miyashiro JK, Poppa V. Berk BC. Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ Res, 1997, 81(3):311-9.
23. 姜宗来, 冀凯宏, 杨向群, 等. 自发性高血压大鼠胸主动脉结构重建和力学特性. 生物医学工程学杂志, 2000, 17(1):66-70.
24. Buus CL, Pourageaud F, Fazzi GE, Janssen G, Mulvany MJ, De Mey JG. Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries. Circ Res, 2001, 89(2):180-6.
25. Pourageaud F, De Mey JG.. Vasomotor responses in chronically hyperperfused and hypoperfused rat mesenteric arteries. Am J Physiol, 1998, 274:H1301–H1307.
26. Langille BL, Bendeck MP, Keeley FW. Adaptation of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Physiol, 1989, 256:H931–H939.
27. Cho A, Mitchell L, Koopmans D, Langille BL. Effects of changes in blood flow rate on cell death and cell proliferation in carotid arteries of immature rabbits. Circ Res, 1997, 81: 328-337.
28. Best PJ, Hasdai D, Sangiorgi G, Schwartz RS, Holmes DR Jr, Simari RD, Lerman A. Apoptosis: basic concepts and implications in coronary artery disease. Arterioscler Thromb Vasc Biol, 1999, 19:14 –22.
29. Hamet P, DeBlois D, Dam TV, Richard L, Teiger E, Tea BS, Orlov SN, Tremblay J. Apoptosis and vascular wall remodeling in hypertension. Can J Physiol Pharmacol, 1996, 74:850–861.
30. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev, 1995, 75:487–517.
31. Fung YC. Biomechanics: Motion, Flow, Stress, and Growth. New York: Springer Verlag, 1990.
1. VanderLaan, P.A., Reardon, C.A., Getz, G.S. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler. Thromb. Vasc. Biol, 2004, 24:12-22.
2. Cheng, C., Tempel, D., van Haperen, R., van der Baan, A., Grosveld, F., Daemen, M.J., Krams, R., de Crom, R. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation, 2006, 113:2744-53.
3. Van Hinsbergh, W.M. Endothelial Permeability for Macromolecules Mechanistic Aspects of Pathophysiological Modulation. Arterioscler. Thromb. Vasc. Biol, 1997, 17:1018-23.
4. Schwenke, D.C., Carew, T.E. Initiation of atherosclerotic lesions in cholesterol fed rabbits. Arteriosclerosis, 1989, 9:908–18
5. Tada, S., Tarbell, J.M. The internal elastic lamina affects the distribution of macromolecules in the arterial wall: a computational study. Am. J. Physiol. Heart. Circ. Physiol, 2004, 287:H905–H913.
6. Lee, K., Forudi, F., Saidel, G.M., Penn, M.S. Alterations in internal elastic lamina permeability as a function of age and anatomical site precede lesion development in apolipoprotein E-null mice. Circ Res, 2005, 97:450-6.
7. Wong, L.C., Langille, B.L. Developmental remodeling of the internal elastic lamina of rabbit arteries: effect of blood flow. Circ. Res, 1996, 78:799-805.
8. Bezie, Y., Lamaziere, J.M., Laurent, S., Challande, P., Cunha, R.S., Bonnet, J., Lacolley, P. Fibronectin expression and aortic wall elastic modulus in spontaneously hypertensive rats. Arterioscler Thromb. Vasc. Biol, 1998, 18:1027–1034.
9. Laurent, S., Boutouyrie, P., Lacolley, P. Structural and genetic bases of arterial stiffness. Hypertension, 2005, 45:1050-5.
10. Penn, M.S., Chisolm, G.M. Relation between lipopolysaccharide-induced endothelial cell injury and entry of macromolecules into the rat aorta in vivo. Circ. Res, 1991 68:1259-69.
11. Fry, D.L.. Mass transport, atherogenesis, and risk. Arteriosclerosis, 1987, 7: 88-100.
12. Weinbaum, S., Tzeghai, G., Ganatos, P., Pfeffer, R., Chien, S. Effect of cell turnover and leaky junctions on arterial macromolecular transport. Am. J. Physiol, 1985, 248:H945-H960.
13. Huang Y, Jan KM, Rumschitzki D, Weinbaum S. Structural changes in rat aortic intima due to transmural pressure. J Biomech Eng, 1998, 120:476-83.
14. Huang Y, Rumschitzki D, Chien S, Weinbaum S. A fiber matrix model for the filtration through fenestral pores in a compressible arterial intima. Am J Physiol, 1997, 272:23-39.
15. Lanir Y. The possible role of intimal convective transport in atherogenesis. Biorheology, 1984, 21:643-7.
16. Boumaza S, Arribas SM, Osborne-Pellegrin M, McGrath JC, Laurent S, Lacolley P, Challande P. Fenestrations of the carotid internal elastic lamina and structural adaptation in stroke-prone spontaneously hypertensive rats. Hypertension, 2001, 37(4):1101-7.
17. Miyashiro, J.K., Poppa, V., Berk, B.C. Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ. Res, 1997, 81:311-9.
18. Khan, B.V., Parthasarathy, S.S., Alexander, R.W., Medford, R.M. Modified low density lipoprotein and its constituents augment ytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J. Clin. Invest, 1995, 95:262-70.
19. Tarbell JM. Mass transport in arteries and the localization of atherosclerosis. Annu Rev Biomed Eng, 2003. 5:79-118.
20. Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., Witztum, J.L. Beyond cholesterol.Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J Med, 1989, 14:915–924.
1. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev, 2004, 84(3):767-801.
2. Thyberg J. Differentiated properties and proliferation of arterial smooth muscle cells in culture. Int Rev Cytol, 1996, 169:183-265.
3. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev, 1995, 75(3):487-517.
4. Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res, 2006, 69(3):614-24.
5. Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev, 2000, 14(17):2123-33.
6. Lijnen HR. Metalloproteinases in development and progression of vascular disease. Pathophysiol Haemost Thromb, 2003, 33:275-81.
7. Kuzuya M, Iguchi A. Role of matrix metalloproteinases in vascular remodeling. J Atheroscler Thromb, 2003, 10(5):275-82.
8. Bassiouny HS, Song RH, Hong XF, Singh A, Kocharyan H, Glagov S. Flow regulation of 72-kD collagenase IV (MMP-2) after experimental arterial injury. Circulation, 1998, 98(2):157-63.
9. Garcia-Touchard A, Henry TD, Sangiorgi G, Spagnoli LG, Mauriello A, Conover C, Schwartz RS. Extracellular proteases in atherosclerosis and restenosis. Arterioscler Thromb Vasc Biol, 2005, 25(6):1119-27.
10. Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta EG, et al. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requirestype IV collagenase activity and is inhibited by cellular differentiation. Circ Res, 1994, 75(1):41-54.
11. Ikonomidis JS, Barbour JR, Amani Z, Stroud RE, Herron AR, McClister DM Jr, Camens SE, Lindsey ML, Mukherjee R, Spinale FG. Effects of deletion of the matrix metalloproteinase 2 gene on development of murine thoracic aortic aneurysms. Circulation, 2005, 112(9 Suppl):I242-8.
12. Kim MM, Ta QV, Mendis E, Rajapakse N, Jung WK, Byun HG, Jeon YJ, Kim SK. Phlorotannins in Ecklonia cava extract inhibit matrix metalloproteinase activity. Life Sci. 2006, 79(15):1436-43.
13. Sho E, Chu J, Sho M, Fernandes B, Judd D, Ganesan P, Kimura H, Dalman RL. Continuous periaortic infusion improves doxycycline efficacy in experimental aortic aneurysms. J Vasc Surg, 2004, 39(6):1312-21.
14. Nair RR, Solway J, Boyd DD. Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J Biol Chem, 2006, 281(36):26424-36.
15. Cai WJ, Kocsis E, Wu X, Rodriguez M, Luo X, Schaper W, Schaper J. Remodeling of the vascular tunica media is essential for development of collateral vessels in the canine heart. Mol Cell Biochem, 2004, 264(1-2):201-10.
16. Storz P, Toker A. 3'-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling. Front Biosci, 2002, 1(7):886-902.
17. Risinger GM Jr, Hunt TS, Updike DL, Bullen EC, Howard EW. Matrix metalloproteinase-2 expression by vascular smooth muscle cells is mediated by both stimulatory and inhibitory signals in response to growth factors. J Biol Chem, 2006, 281(36):25915-25.
18. Yao JS, Shen F, Young WL, Yang GY. Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int, 2007, 50(3):524-30.
19. Lee KS, Jin SM, Kim SS, Lee YC. Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma. J Allergy Clin Immunol, 2004, 113(5):902-9.
20. Stabile E, Zhou YF, Saji M, Castagna M, Shou M, Kinnaird TD, Baffour R, Ringel MD, Epstein SE, Fuchs S. Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit. Circ Res, 2003, 93(11):1059-65.
21. Bunton TE, Biery NJ, Myers L, Gayraud B, Ramirez F, Dietz HC. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ Res, 2001, 88(1):37-43.
22. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia, 2003, 17(3):590-603.
23. Kim TJ, Yun YP. Antiproliferative activity of NQ304, a synthetic 1,4-naphthoquinone, is mediated via the suppressions of the PI3K/Akt and ERK1/2 signaling pathways in PDGF-BB-stimulated vascular smooth muscle cells. Vascul Pharmacol, 2007, 46(1):43-51.
24. Yao JS, Shen F, Young WL, Yang GY. Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int, 2007, 50(3):524-30.
25. Mullany LK, Nelsen CJ, Hanse EA, Goggin MM, Anttila CK, Peterson M, Bitterman PB, Raghavan A, Crary GS, Albrecht JH. Akt-mediated liver growth promotes induction of cyclin E through a novel translational mechanism and a p21-mediated cell cycle arrest. J Biol Chem, 2007, 282(29):21244-52.
26. Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, Eshraghi M, Manda KD, Wiechec E, Los M. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat, 2007, 10(1-2):13-29.
27. Kim HJ, Park SR, Park HJ, Choi BH, Min BH. Potential predictive markers for proliferative capacity of cultured human articular chondrocytes: PCNA and p21. Artif Organs, 2005, 29(5):393-8.
1. Resnick N, Yahav H, Shay-Salit A, Shushy M, Schubert S, Zilberman LC, Wofovitz E. Fluid shear stress and the vascular endothelium: for better and for worse. Prog Biophys Mol Biol, 2003, 81:177–199.
2. Gotlieb AI, Silver MD. Cardiovascular Pathology, 3rd edn. Churchill-Livingstone: New York, NY, 2001.
3. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Atherosclerosis V: the Fifth Saratoga Conference, 2000, 902:230–240.
4. Landmesser U, Hornig B, Drexler H. Endothelial function—a critical determinant in atherosclerosis? Circulation, 2004, 109:27–33.
5. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation, 2002, 106:653–658.
6. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. Lea and Febiger: Philadelphia, 1990.
7. Tada S, Tarbell JM. Interstitial flow through the internal elastic lamina affects shear stress on arterial smooth muscle cells. Am J Physiol Heart Circ Physiol, 2000, 278(5):H1589-97.
8. Ibrahim J, Miyashiro JK, Berk BC. Shear stress is differentially regulated among inbred rat strains. Circ Res, 2003, 92:1001–1009.
9. Korshunov VA, Berk BC. Strain-dependent vascular remodeling—The ‘Glagov phenomenon’ is genetically determined. Circulation, 2004, 110:220–226.
10. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med, 2002, 8:1249–1256.
11. Campbell GJ, Eng P, Roach MR. Fenestrations in the internal elastic lamina at bifurcations of human cerebral-arteries. Stroke, 1981, 12:489–496.
12. Akimoto S, Mitsumata M, Sasaguri T, Yoshida Y. Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1). Circ Res, 2000, 86:185–190.
13. Chiu JJ, Chen LJ, Chen CN, Lee PL, Lee CI. A model for studying the effect of shear stress on interactions between vascular endothelial cells and smooth muscle cells. J Biomech, 2004, 37:531–539.
14. Niwa K, Kado T, Sakai J, Karino T. The effects of a shear flow on the uptake of LDL and acetylated LDL by an EC monoculture and an EC-SMC coculture. Ann Biomed Eng, 2004, 32:537–543.
15. Liu SQ, Tang D, Tieche C, Alkema PK. Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: mediation by gradient of cell density. Am J Physiol—Heart Circ Physiol, 2003, 285:H1072–H1080.
16. Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium. Physiol Rev, 2001, 81:1415–1459.
17. Brakemeier S, Kersten A, Eichler I, Grgic I, Zakrzewicz A, Hopp H, K?hler R, Hoyer J. Shear stress-induced up-regulation of the intermediate conductance Ca2+-activated K+ channel in human endothelium. Cardiovasc Res, 2003, 60:488–496.
18. Lieu DK, Pappone PA, Barakat AI. Differential membrane potential and ion current responses to different types of shear stress in vascular endothelial cells. Am J Physiol—Cell Physiol, 2004, 286:C1367–C1375.
19. Mccue S, Noria S, Langille BL. Shear-induced reorganization of endothelial cell cytoskeleton and adhesion complexes. Trends Cardiovasc Med, 2004, 14:143–151.
20. Shyy JY, Chien S. Role of integrins in endothelial mechanosensing of shear stress. Circ Res, 2002, 91:769–775.
21. Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res, 2003,93:E136–E142.
22. Gudi S, Huvar I, White CR, McKnight NL, Dusserre N, Boss GR, Frangos JA. Rapid activation of Ras by fluid flow is mediated by G alpha(q) and G beta gamma subunits of heterotrimeric G proteins in human endothelial cells. Arteriosclerosis Thrombosis Vasc Biol, 2003, 23:994–1000.
23. Zuluaga S, Alvarez-Barrientos A, Gutiérrez-Uzquiza A, Benito M, Nebreda AR, Porras A. Negative regulation of Akt activity by p38alpha MAP kinase in cardiomyocytes involves membrane localization of PP2A through interaction with caveolin-1. Cell Signal, 2007, 19(1):62-74.
24. Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol Genom, 2002, 9:27–41.
25. Passerini AG, Polacek DC, Shi C, Francesco NM, Manduchi E, Grant GR, Pritchard WF, Powell S, Chang GY, Stoeckert CJ Jr, Davies PF. Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta. Proc Natl Acad Sci USA, 2004, 101:2482–2487.
26. Li YS, Haga JH, Chien S. Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech, 2005, 38(10):1949-71.
27. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci USA, 2000, 97:9052–9057.
28. Choi HW, Barakat AI. Numerical study of the impact of non-Newtonian blood behavior on flow over a two-dimensional backward facing step. Biorheology, 2005,42(6):493-509
29. Dancu MB, Berardi DE, Vanden Heuvel JP, Tarbell JM. Atherogenic Endothelial Cell eNOS and ET-1 Responses to Asynchronous Hemodynamics are Mitigated by Conjugated Linoleic Acid. Ann Biomed Eng, 2007, 35(7):1111-9.
30. Chen XL, Varner SE, Rao AS, Grey JY, Thomas S, Cook CK, Wasserman MA, Medford RM, Jaiswal AK, Kunsch C. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells—a novel anti-inflammatory mechanism. J Biol Chem, 2003, 278:703–711.
31. Liu Y, Zhu Y, Rannou F, Lee TS, Formentin K, Zeng L, Yuan X, Wang N, Chien S, Forman BM, Shyy JY. Laminar flow activates peroxisome proliferator-activated receptor-gamma in vascular endothelial cells. Circulation, 2004, 110: 1128–1133.
32. Ni CW, Hsieh HJ, Chao YJ, Wang DL. Shear flow attenuates serum-induced STAT3 activation in endothelial cells. J Biol Chem, 2003, 278:19702–19708.
33. Chiu JJ, Lee PL, Chen CN, Lee CI, Chang SF, Chen LJ, Lien SC, Ko YC, Usami S, Chien S. Shear stress increases ICAM-1 and decreases VCAM-1 and E-selectin expressions induced by tumor necrosis factor-alpha in endothelial cells. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:73–79.
34. Cheng C, Tempel D, van Haperen R, van der Baan A, Grosveld F, Daemen MJ, Krams R, de Crom R. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation, 2006, 113(23):2744-53.
35. Sheikh S, Rainger GE, Gale Z, Rahman M, Nash GB. Exposure to fluid shear stress modulates the ability of endothelial cells to recruit neutrophils in response to tumor necrosis factor-alpha: a basis for local variations in vascular sensitivity to inflammation. Blood, 2003, 102:2828–2834.
36. Yamawaki H, Lehoux S, Berk BC. Chronic physiological shear stress inhibits tumor necrosis factorinduced proinflammatory responses in rabbit aorta perfused ex vivo. Circulation, 2003, 108:1619–1625.
37. Chiu JJ, Chen LJ, Lee PL, Lee CI, Lo LW, Usami S, Chien S. Shear stress inhibits adhesion molecule expression in vascular endothelial cells induced by coculture with smooth muscle cells. Blood, 2003, 101:2667–2674.
38. Sorescu GP, Sykes M, Weiss D, Platt MO, Saha A, Hwang J, Boyd N, Boo YC, Vega JD, Taylor WR, Jo H. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response.J Biol Chem, 2003, 278:31128–31135.
39. Rubanyi GM, Romero JC, Vanhoutte PM. Flow induced release of endothelium-derived relaxing factor. Am J Physiol, 1986, 250:1145–1149.
40. Awolesi MA, Widmann MD, Sessa WC, Sumpio BE. Cyclic strain increases endothelial nitric-oxide synthase activity. Surgery, 1994, 116:439–445.
41. Li J, Billiar TR, Talanian RV, Kim YM. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Commun, 1997, 240:419–424.
42. Freedman JE, Sauter R, Battinelli EM, Ault K, Knowles C, Huang PL, Loscalzo J. Deficient platelet-derived nitric oxide and enhanced hemostasis in mice lacking the NOSIII gene. Circ Res, 1999, 84:1416–1421.
43. Casas JP, Bautista LE, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation, 2004, 109:1359–1365.
44. Feron O, Smith TW, Michel T, Kelly RA. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem, 1997, 272:17744–17748.
45. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, Marsden PA. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arteriosclerosis Thrombosis Vasc Biol, 1997, 17: 2479–2488.
46. Peng HB, Libby P, Liao JK. Induction and stabilization of I-kappa-B-alpha by nitric-oxide mediates inhibition of Nf-kappa-B. J Biol Chem, 1995, 270:14214–14219.
47. Ju H, Zou R, Venema VJ. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem, 1997, 272: 18522–18525.
48. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol—Regul Integrative Comp Physiol, 2003, 284:R1–R12.
49. Marcun Varda N, Zagradisnik B, Herodez SS, Kokalj Vokac N, Gregoric A. Polymorphisms in four candidate genes in young patients with essential hypertension. Acta Paediatr, 2006, 95(3):353-8.
50. Camp ER, Yang A, Liu W, Fan F, Somcio R, Hicklin DJ, Ellis LM. Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in vivo model of pancreatic cancer. Clin Cancer Res, 2006, 12(8):2628-33.
51. Kaufman DA, Albelda SM, Sun J, Davies PF. Role of lateral cell–cell border location and extracellular/transmembrane domains in PECAM/CD31 mechanosensation. Biochem Biophys Res Commun, 2004, 320:1076–1081.
52. Boo YC, Sorescu GP, Bauer PM, Fulton D, Kemp BE, Harrison DG, Sessa WC, Jo H. Endothelial NO synthase phosphorylated at Ser (635) produces no without requiring intracellular calcium increase. Free Radical Biol Med, 2003, 35:729–741.
53. Boo YC, Jo H. Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases. Am J Physiol—Cell Physiol, 2003, 285:C499–C508.
54. Zhu W, Smart EJ. Myristic acid stimulates endothelial nitric-oxide synthase in a CD36- and an AMP kinase-dependent manner. J Biol Chem, 2005, 280(33):29543-50.
55. Davis ME, Cai H, McCann L, Fukai T, Harrison DG. Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training. Am J Physiol—Heart Circ Physiol, 2003, 284:H1449–H1453.
56. Hambrecht R, Adams V, Erbs S, Linke A, Kr?nkel N, Shu Y, Baither Y, Gielen S, Thiele H, Gummert JF, Mohr FW, Schuler G. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation, 2003, 107:3152–3158.
57. Hoffmann J, Dimmeler S, Haendeler J. Shear stress increases the amount of S-nitrosylated molecules in endothelial cells: important role for signal transduction. FEBS Lett, 2003, 551:153–158.
58. Martin S, Tesse A, Hugel B, Martínez MC, Morel O, Freyssinet JM, Andriantsitohaina R. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation, 2004, 109:1653–1659.
59. Cattaruzza M, Guzik TJ, S?odowski W, Pelvan A, Becker J, Halle M, Buchwald AB, Channon KM, Hecker M. Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease. Circ Res, 2004, 95:841–847.
60. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol—Regul Integrative Comp Physiol, 2003, 285:R277–R297.
61. Rodríguez C, Raposo B, Martínez-González J, Casaní L, Badimon L. Low density lipoproteins downregulate lysyl oxidase in vascular endothelial cells and the arterial wall. Arteriosclerosis Thrombosis Vasc Biol, 2002, 22:1409–1414.
62. Hwang J, Saha A, Boo YC, Sorescu GP, McNally JS, Holland SM, Dikalov S, Giddens DP, Griendling KK, Harrison DG, Jo H. Oscillatory shear stress stimulates endothelial production of O2- from p47(phox)-dependent NAD(P)H oxidases, leading to monocyte adhesion. J Biol Chem, 2003, 278: 47291–47298.
63. Touyz RM, Schiffrin EL. Ang II-stimulated generation of vascular smooth muscle cell reactive oxygen species is increased in human hypertension: role of phospholipase D. Circulation, 1999, 100:479.
64. De Keulenaer GW, Chappell DC, Ishizaka N, Nerem RM, Alexander RW, Griendling KK. Oscillatory and steady laminar shear stress differentially affect human endothelial redox state—role of a superoxide-producing NADH oxidase. Circ Res, 1998, 82:1094–1101.
65. Hwang J, Ing MH, Salazar A, Lassègue B, Griendling K, Navab M, Sevanian A, Hsiai TK. Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression—implication for native LDL oxidation. Circ Res, 2003, 93:1225–1232.
66. Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, TsikasD, Ertl G, Bauersachs J. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007, 56(3):666-74.
67. Hermann C, Zeiher AM, Dimmeler S. Shear stress induced up-regulation of superoxide dismutase inhibits tumor necrosis factor alpha-mediated apoptosis of endothelial cells. Circulation, 1997, 96:2732.
68. Horiuchi M, Tsutsui M, Tasaki H, Morishita T, Suda O, Nakata S, Nihei S, Miyamoto M, Kouzuma R, Okazaki M, Yanagihara N, Adachi T, Nakashima Y. Upregulation of vascular extracellular superoxide dismutase in patients with acute coronary syndromes. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:106–111.
69. Jaimes EA, DeMaster EG, Tian RX, Raij L..Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:1031–1036.
70. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Br?sen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, B?hm M, Meinertz T, Münzel T. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis—evidence for involvement of the renin–angiotensin system. Circulation, 1999, 99:2027–2033.
71. Balletshofer BM, Goebbel S, Rittig K, Enderle M, Schmolzer I, Wascher TC, Ferenc Pap A, Westermeier T, Petzinna D, Matthaei S, Haring HU. Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes--a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial. Exp Clin Endocrinol Diabetes, 2005, 113(6):324-30. .
72. de Nigris F, Lerman A, Ignarro LJ, Williams-Ignarro S, Sica V, Baker AH, Lerman LO, Geng YJ, Napoli C. Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis. Trends Mol Med, 2003, 9:351–359.
73. Iuliano L, Mauriello A, Sbarigia E, Spagnoli LG, Violi F. Vitamin E supplementation in patients with carotid atherosclerosis—reversal of alteredoxidative stress status in plasma but not in plaque. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:136–140.
74. Bonello S, Z?hringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, G?rlach A. Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol, 2007, 27(4):755-61.
75. Weinberg PD. Rate-limiting steps in the development of atherosclerosis: the response – to - influx theory. J Vasc Res, 2004, 41:1–17.
76. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis—site-selective responses to atherosclerotic modulators. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:12–22.
77. Himburg HA, Grzybowski DM, Hazel AL, LaMack JA, Li XM, Friedman MH. Spatial comparison between wall shear stress measures and porcine arterial endothelial permeability. Am J Physiol—Heart Circ Physiol, 2004, 286: H1916–H1922.
78. Colangelo S, Langille BL, Gotlieb AI. Patterns of distribution characterize the organization of endothelial microfilaments at aortic flow dividers. Cell Tissue Res, 1994, 278:235–242.
79. Noria S, Cowan DB, Gotlieb AI, Langille BL. Transient and steady-state effects of shear stress on endothelial cell adherens junctions. Circ Res, 1999, 85:504–514.
80. Langille BL, Graham JJ, Kim D, Gotlieb AI. Dynamics of shear-induced redistribution of F-actin in endothelial-cells in vivo. Arteriosclerosis Thrombosis 1991, 11:1814–1820.
81. Noria S, Xu F, McCue S, Jones M, Gotlieb AI, Langille BL. Assembly and reorientation of stress fibers drives morphological changes to endothelial cells exposed to shear stress. Am J Pathol, 2004, 164:1211–1223.
82. Dickson BC, Gotlieb AI. Endothelial dysfunction and repair in the pathogenesis of stable and unstable fibroinflammatory atheromas. Can J Cardiol, 2004, 20:16B–23B.
83. Colangelo S, Langille BL, Steiner G, Gotlieb AI. Alterations in endothelial F-actin microfilaments in rabbit aorta in hypercholesterolemia. Arteriosclerosis Thrombosis Vasc Biol, 1998, 18:52–56.
84. Lin T, Zeng L, Liu Y, DeFea K, Schwartz MA, Chien S, Shyy JY. Rho-ROCK-CIMK-Cofilin pathway regulates shear stress activation of sterol regulatory element binding proteins. Circ Res, 2003, 92:1296–1304.
2. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol, 2004, 24(1):12-22.
3. Wissler RW, Strong JP. Risk factors and progression of atherosclerosis in youth. PDAY Research Group. Pathological Determinants of Atherosclerosis in Youth. Am J Pathol, 1998, 153(4):1023-33.
4. Wyttenbach R, Gallino A, Alerci M, Mahler F, Cozzi L, Di Valentino M, Badimon JJ, Fuster V, Corti R. Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery by noninvasive magnetic resonance imaging. Circulation, 2004, 110(9):1156-61.
5. Friedman MH, Bargeron CB, Deters OJ, Hutchins GM, Mark FF. Correlation between wall shear and intimal thickness at a coronary artery branch. Atherosclerosis, 1987, 68(1-2):27-33.
6. Ku DN, Giddens DP, Zarins CK, Glagov S. Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis, 1985, 5(3):293-302.
7. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci, 2000, 902:230-9.
8. Davies PF. Spatial hemodynamics, the endothelium, and focal atherogenesis: a cell cycle link? Circ Res, 2000, 86(2):114-6.
9. Chien S, Li S, Shyy YJ. Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension, 1998, 31(1 Pt 2):162-9.
10. Berk BC, Abe JI, Min W, Surapisitchat J, Yan C. Endothelial atheroprotective and anti-inflammatory mechanisms. Ann N Y Acad Sci, 2001, 947:93-109.
11. Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol, 1980, 239:H14-H21.
12. Langille BL, O'Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science, 1986, 231: 405-7.
13. Ji JY, Jing H, Diamond SL. Shear stress causes nuclear localization of endothelial glucocorticoid receptor and expression from the GRE promoter. Circ Res, 2003, 92(3):279-85.
14. Endemann G, Abe Y, Bryant CM, Feng Y, Smith CW, Liu DY. Novel anti-inflammatory compounds induce shedding of L-selectin and block primary capture of neutrophils under flow conditions. J Immunol, 1997, 158(10):4879-85.
15. Guzman LA, Mick MJ, Arnold AM, Forudi F, Whitlow PL. Role of intimal hyperplasia and arterial remodeling after balloon angioplasty: an experimental study in the atherosclerotic rabbit model. Arterioscler Thromb Vasc Biol, 1996, 16:479-487.
16. Sho E, Nanjo H, Sho M, Kobayashi M, Komatsu M, Kawamura K, Xu C, Zarins CK, Masuda H. Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress. J Vasc Surg. 2004, 39:601-12.
17. Wolf C, Cai WJ, Vosschulte R, Koltai S, Mousavipour D, Scholz D, Afsah-Hedjri A, Schaper W, Schaper J. Vascular remodeling and altered protein expression during growth of coronary collateral arteries. J Mol Cell Cardiol, 1998, 30: 2291–2305.
18. Tulis DA, Unthank JL, Prewitt RL. Flow-induced arterial remodeling in rat mesenteric vasculature. Am J Physiol, 1998, 274: H874–H882.
19. Groves J, Wang Z, Newman WH. Two distinct phenotypes of rat vascularsmooth muscle cells: growth rate and Production of tumor necrosis factor-alpha. Am Surg, 2005, 71(7):546-50.
20. Su BY, Shontz KM, Flavahan NA, Nowicki PT. The effect of phenotype on mechanical stretch-induced vascular smooth muscle cell apoptosis. J Vasc Res, 2006, 43(3):229-37.
21. Fung YC. Biodynamics: Circulation. New York: Springer Verlag, 1984.54-63.
22. Miyashiro JK, Poppa V. Berk BC. Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ Res, 1997, 81(3):311-9.
23. 姜宗来, 冀凯宏, 杨向群, 等. 自发性高血压大鼠胸主动脉结构重建和力学特性. 生物医学工程学杂志, 2000, 17(1):66-70.
24. Buus CL, Pourageaud F, Fazzi GE, Janssen G, Mulvany MJ, De Mey JG. Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries. Circ Res, 2001, 89(2):180-6.
25. Pourageaud F, De Mey JG.. Vasomotor responses in chronically hyperperfused and hypoperfused rat mesenteric arteries. Am J Physiol, 1998, 274:H1301–H1307.
26. Langille BL, Bendeck MP, Keeley FW. Adaptation of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Physiol, 1989, 256:H931–H939.
27. Cho A, Mitchell L, Koopmans D, Langille BL. Effects of changes in blood flow rate on cell death and cell proliferation in carotid arteries of immature rabbits. Circ Res, 1997, 81: 328-337.
28. Best PJ, Hasdai D, Sangiorgi G, Schwartz RS, Holmes DR Jr, Simari RD, Lerman A. Apoptosis: basic concepts and implications in coronary artery disease. Arterioscler Thromb Vasc Biol, 1999, 19:14 –22.
29. Hamet P, DeBlois D, Dam TV, Richard L, Teiger E, Tea BS, Orlov SN, Tremblay J. Apoptosis and vascular wall remodeling in hypertension. Can J Physiol Pharmacol, 1996, 74:850–861.
30. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev, 1995, 75:487–517.
31. Fung YC. Biomechanics: Motion, Flow, Stress, and Growth. New York: Springer Verlag, 1990.
1. VanderLaan, P.A., Reardon, C.A., Getz, G.S. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler. Thromb. Vasc. Biol, 2004, 24:12-22.
2. Cheng, C., Tempel, D., van Haperen, R., van der Baan, A., Grosveld, F., Daemen, M.J., Krams, R., de Crom, R. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation, 2006, 113:2744-53.
3. Van Hinsbergh, W.M. Endothelial Permeability for Macromolecules Mechanistic Aspects of Pathophysiological Modulation. Arterioscler. Thromb. Vasc. Biol, 1997, 17:1018-23.
4. Schwenke, D.C., Carew, T.E. Initiation of atherosclerotic lesions in cholesterol fed rabbits. Arteriosclerosis, 1989, 9:908–18
5. Tada, S., Tarbell, J.M. The internal elastic lamina affects the distribution of macromolecules in the arterial wall: a computational study. Am. J. Physiol. Heart. Circ. Physiol, 2004, 287:H905–H913.
6. Lee, K., Forudi, F., Saidel, G.M., Penn, M.S. Alterations in internal elastic lamina permeability as a function of age and anatomical site precede lesion development in apolipoprotein E-null mice. Circ Res, 2005, 97:450-6.
7. Wong, L.C., Langille, B.L. Developmental remodeling of the internal elastic lamina of rabbit arteries: effect of blood flow. Circ. Res, 1996, 78:799-805.
8. Bezie, Y., Lamaziere, J.M., Laurent, S., Challande, P., Cunha, R.S., Bonnet, J., Lacolley, P. Fibronectin expression and aortic wall elastic modulus in spontaneously hypertensive rats. Arterioscler Thromb. Vasc. Biol, 1998, 18:1027–1034.
9. Laurent, S., Boutouyrie, P., Lacolley, P. Structural and genetic bases of arterial stiffness. Hypertension, 2005, 45:1050-5.
10. Penn, M.S., Chisolm, G.M. Relation between lipopolysaccharide-induced endothelial cell injury and entry of macromolecules into the rat aorta in vivo. Circ. Res, 1991 68:1259-69.
11. Fry, D.L.. Mass transport, atherogenesis, and risk. Arteriosclerosis, 1987, 7: 88-100.
12. Weinbaum, S., Tzeghai, G., Ganatos, P., Pfeffer, R., Chien, S. Effect of cell turnover and leaky junctions on arterial macromolecular transport. Am. J. Physiol, 1985, 248:H945-H960.
13. Huang Y, Jan KM, Rumschitzki D, Weinbaum S. Structural changes in rat aortic intima due to transmural pressure. J Biomech Eng, 1998, 120:476-83.
14. Huang Y, Rumschitzki D, Chien S, Weinbaum S. A fiber matrix model for the filtration through fenestral pores in a compressible arterial intima. Am J Physiol, 1997, 272:23-39.
15. Lanir Y. The possible role of intimal convective transport in atherogenesis. Biorheology, 1984, 21:643-7.
16. Boumaza S, Arribas SM, Osborne-Pellegrin M, McGrath JC, Laurent S, Lacolley P, Challande P. Fenestrations of the carotid internal elastic lamina and structural adaptation in stroke-prone spontaneously hypertensive rats. Hypertension, 2001, 37(4):1101-7.
17. Miyashiro, J.K., Poppa, V., Berk, B.C. Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ. Res, 1997, 81:311-9.
18. Khan, B.V., Parthasarathy, S.S., Alexander, R.W., Medford, R.M. Modified low density lipoprotein and its constituents augment ytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J. Clin. Invest, 1995, 95:262-70.
19. Tarbell JM. Mass transport in arteries and the localization of atherosclerosis. Annu Rev Biomed Eng, 2003. 5:79-118.
20. Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., Witztum, J.L. Beyond cholesterol.Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J Med, 1989, 14:915–924.
1. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev, 2004, 84(3):767-801.
2. Thyberg J. Differentiated properties and proliferation of arterial smooth muscle cells in culture. Int Rev Cytol, 1996, 169:183-265.
3. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev, 1995, 75(3):487-517.
4. Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res, 2006, 69(3):614-24.
5. Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev, 2000, 14(17):2123-33.
6. Lijnen HR. Metalloproteinases in development and progression of vascular disease. Pathophysiol Haemost Thromb, 2003, 33:275-81.
7. Kuzuya M, Iguchi A. Role of matrix metalloproteinases in vascular remodeling. J Atheroscler Thromb, 2003, 10(5):275-82.
8. Bassiouny HS, Song RH, Hong XF, Singh A, Kocharyan H, Glagov S. Flow regulation of 72-kD collagenase IV (MMP-2) after experimental arterial injury. Circulation, 1998, 98(2):157-63.
9. Garcia-Touchard A, Henry TD, Sangiorgi G, Spagnoli LG, Mauriello A, Conover C, Schwartz RS. Extracellular proteases in atherosclerosis and restenosis. Arterioscler Thromb Vasc Biol, 2005, 25(6):1119-27.
10. Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta EG, et al. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requirestype IV collagenase activity and is inhibited by cellular differentiation. Circ Res, 1994, 75(1):41-54.
11. Ikonomidis JS, Barbour JR, Amani Z, Stroud RE, Herron AR, McClister DM Jr, Camens SE, Lindsey ML, Mukherjee R, Spinale FG. Effects of deletion of the matrix metalloproteinase 2 gene on development of murine thoracic aortic aneurysms. Circulation, 2005, 112(9 Suppl):I242-8.
12. Kim MM, Ta QV, Mendis E, Rajapakse N, Jung WK, Byun HG, Jeon YJ, Kim SK. Phlorotannins in Ecklonia cava extract inhibit matrix metalloproteinase activity. Life Sci. 2006, 79(15):1436-43.
13. Sho E, Chu J, Sho M, Fernandes B, Judd D, Ganesan P, Kimura H, Dalman RL. Continuous periaortic infusion improves doxycycline efficacy in experimental aortic aneurysms. J Vasc Surg, 2004, 39(6):1312-21.
14. Nair RR, Solway J, Boyd DD. Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J Biol Chem, 2006, 281(36):26424-36.
15. Cai WJ, Kocsis E, Wu X, Rodriguez M, Luo X, Schaper W, Schaper J. Remodeling of the vascular tunica media is essential for development of collateral vessels in the canine heart. Mol Cell Biochem, 2004, 264(1-2):201-10.
16. Storz P, Toker A. 3'-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling. Front Biosci, 2002, 1(7):886-902.
17. Risinger GM Jr, Hunt TS, Updike DL, Bullen EC, Howard EW. Matrix metalloproteinase-2 expression by vascular smooth muscle cells is mediated by both stimulatory and inhibitory signals in response to growth factors. J Biol Chem, 2006, 281(36):25915-25.
18. Yao JS, Shen F, Young WL, Yang GY. Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int, 2007, 50(3):524-30.
19. Lee KS, Jin SM, Kim SS, Lee YC. Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma. J Allergy Clin Immunol, 2004, 113(5):902-9.
20. Stabile E, Zhou YF, Saji M, Castagna M, Shou M, Kinnaird TD, Baffour R, Ringel MD, Epstein SE, Fuchs S. Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit. Circ Res, 2003, 93(11):1059-65.
21. Bunton TE, Biery NJ, Myers L, Gayraud B, Ramirez F, Dietz HC. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ Res, 2001, 88(1):37-43.
22. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia, 2003, 17(3):590-603.
23. Kim TJ, Yun YP. Antiproliferative activity of NQ304, a synthetic 1,4-naphthoquinone, is mediated via the suppressions of the PI3K/Akt and ERK1/2 signaling pathways in PDGF-BB-stimulated vascular smooth muscle cells. Vascul Pharmacol, 2007, 46(1):43-51.
24. Yao JS, Shen F, Young WL, Yang GY. Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int, 2007, 50(3):524-30.
25. Mullany LK, Nelsen CJ, Hanse EA, Goggin MM, Anttila CK, Peterson M, Bitterman PB, Raghavan A, Crary GS, Albrecht JH. Akt-mediated liver growth promotes induction of cyclin E through a novel translational mechanism and a p21-mediated cell cycle arrest. J Biol Chem, 2007, 282(29):21244-52.
26. Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, Eshraghi M, Manda KD, Wiechec E, Los M. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat, 2007, 10(1-2):13-29.
27. Kim HJ, Park SR, Park HJ, Choi BH, Min BH. Potential predictive markers for proliferative capacity of cultured human articular chondrocytes: PCNA and p21. Artif Organs, 2005, 29(5):393-8.
1. Resnick N, Yahav H, Shay-Salit A, Shushy M, Schubert S, Zilberman LC, Wofovitz E. Fluid shear stress and the vascular endothelium: for better and for worse. Prog Biophys Mol Biol, 2003, 81:177–199.
2. Gotlieb AI, Silver MD. Cardiovascular Pathology, 3rd edn. Churchill-Livingstone: New York, NY, 2001.
3. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Atherosclerosis V: the Fifth Saratoga Conference, 2000, 902:230–240.
4. Landmesser U, Hornig B, Drexler H. Endothelial function—a critical determinant in atherosclerosis? Circulation, 2004, 109:27–33.
5. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation, 2002, 106:653–658.
6. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. Lea and Febiger: Philadelphia, 1990.
7. Tada S, Tarbell JM. Interstitial flow through the internal elastic lamina affects shear stress on arterial smooth muscle cells. Am J Physiol Heart Circ Physiol, 2000, 278(5):H1589-97.
8. Ibrahim J, Miyashiro JK, Berk BC. Shear stress is differentially regulated among inbred rat strains. Circ Res, 2003, 92:1001–1009.
9. Korshunov VA, Berk BC. Strain-dependent vascular remodeling—The ‘Glagov phenomenon’ is genetically determined. Circulation, 2004, 110:220–226.
10. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med, 2002, 8:1249–1256.
11. Campbell GJ, Eng P, Roach MR. Fenestrations in the internal elastic lamina at bifurcations of human cerebral-arteries. Stroke, 1981, 12:489–496.
12. Akimoto S, Mitsumata M, Sasaguri T, Yoshida Y. Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1). Circ Res, 2000, 86:185–190.
13. Chiu JJ, Chen LJ, Chen CN, Lee PL, Lee CI. A model for studying the effect of shear stress on interactions between vascular endothelial cells and smooth muscle cells. J Biomech, 2004, 37:531–539.
14. Niwa K, Kado T, Sakai J, Karino T. The effects of a shear flow on the uptake of LDL and acetylated LDL by an EC monoculture and an EC-SMC coculture. Ann Biomed Eng, 2004, 32:537–543.
15. Liu SQ, Tang D, Tieche C, Alkema PK. Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: mediation by gradient of cell density. Am J Physiol—Heart Circ Physiol, 2003, 285:H1072–H1080.
16. Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium. Physiol Rev, 2001, 81:1415–1459.
17. Brakemeier S, Kersten A, Eichler I, Grgic I, Zakrzewicz A, Hopp H, K?hler R, Hoyer J. Shear stress-induced up-regulation of the intermediate conductance Ca2+-activated K+ channel in human endothelium. Cardiovasc Res, 2003, 60:488–496.
18. Lieu DK, Pappone PA, Barakat AI. Differential membrane potential and ion current responses to different types of shear stress in vascular endothelial cells. Am J Physiol—Cell Physiol, 2004, 286:C1367–C1375.
19. Mccue S, Noria S, Langille BL. Shear-induced reorganization of endothelial cell cytoskeleton and adhesion complexes. Trends Cardiovasc Med, 2004, 14:143–151.
20. Shyy JY, Chien S. Role of integrins in endothelial mechanosensing of shear stress. Circ Res, 2002, 91:769–775.
21. Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res, 2003,93:E136–E142.
22. Gudi S, Huvar I, White CR, McKnight NL, Dusserre N, Boss GR, Frangos JA. Rapid activation of Ras by fluid flow is mediated by G alpha(q) and G beta gamma subunits of heterotrimeric G proteins in human endothelial cells. Arteriosclerosis Thrombosis Vasc Biol, 2003, 23:994–1000.
23. Zuluaga S, Alvarez-Barrientos A, Gutiérrez-Uzquiza A, Benito M, Nebreda AR, Porras A. Negative regulation of Akt activity by p38alpha MAP kinase in cardiomyocytes involves membrane localization of PP2A through interaction with caveolin-1. Cell Signal, 2007, 19(1):62-74.
24. Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol Genom, 2002, 9:27–41.
25. Passerini AG, Polacek DC, Shi C, Francesco NM, Manduchi E, Grant GR, Pritchard WF, Powell S, Chang GY, Stoeckert CJ Jr, Davies PF. Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta. Proc Natl Acad Sci USA, 2004, 101:2482–2487.
26. Li YS, Haga JH, Chien S. Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech, 2005, 38(10):1949-71.
27. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci USA, 2000, 97:9052–9057.
28. Choi HW, Barakat AI. Numerical study of the impact of non-Newtonian blood behavior on flow over a two-dimensional backward facing step. Biorheology, 2005,42(6):493-509
29. Dancu MB, Berardi DE, Vanden Heuvel JP, Tarbell JM. Atherogenic Endothelial Cell eNOS and ET-1 Responses to Asynchronous Hemodynamics are Mitigated by Conjugated Linoleic Acid. Ann Biomed Eng, 2007, 35(7):1111-9.
30. Chen XL, Varner SE, Rao AS, Grey JY, Thomas S, Cook CK, Wasserman MA, Medford RM, Jaiswal AK, Kunsch C. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells—a novel anti-inflammatory mechanism. J Biol Chem, 2003, 278:703–711.
31. Liu Y, Zhu Y, Rannou F, Lee TS, Formentin K, Zeng L, Yuan X, Wang N, Chien S, Forman BM, Shyy JY. Laminar flow activates peroxisome proliferator-activated receptor-gamma in vascular endothelial cells. Circulation, 2004, 110: 1128–1133.
32. Ni CW, Hsieh HJ, Chao YJ, Wang DL. Shear flow attenuates serum-induced STAT3 activation in endothelial cells. J Biol Chem, 2003, 278:19702–19708.
33. Chiu JJ, Lee PL, Chen CN, Lee CI, Chang SF, Chen LJ, Lien SC, Ko YC, Usami S, Chien S. Shear stress increases ICAM-1 and decreases VCAM-1 and E-selectin expressions induced by tumor necrosis factor-alpha in endothelial cells. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:73–79.
34. Cheng C, Tempel D, van Haperen R, van der Baan A, Grosveld F, Daemen MJ, Krams R, de Crom R. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation, 2006, 113(23):2744-53.
35. Sheikh S, Rainger GE, Gale Z, Rahman M, Nash GB. Exposure to fluid shear stress modulates the ability of endothelial cells to recruit neutrophils in response to tumor necrosis factor-alpha: a basis for local variations in vascular sensitivity to inflammation. Blood, 2003, 102:2828–2834.
36. Yamawaki H, Lehoux S, Berk BC. Chronic physiological shear stress inhibits tumor necrosis factorinduced proinflammatory responses in rabbit aorta perfused ex vivo. Circulation, 2003, 108:1619–1625.
37. Chiu JJ, Chen LJ, Lee PL, Lee CI, Lo LW, Usami S, Chien S. Shear stress inhibits adhesion molecule expression in vascular endothelial cells induced by coculture with smooth muscle cells. Blood, 2003, 101:2667–2674.
38. Sorescu GP, Sykes M, Weiss D, Platt MO, Saha A, Hwang J, Boyd N, Boo YC, Vega JD, Taylor WR, Jo H. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response.J Biol Chem, 2003, 278:31128–31135.
39. Rubanyi GM, Romero JC, Vanhoutte PM. Flow induced release of endothelium-derived relaxing factor. Am J Physiol, 1986, 250:1145–1149.
40. Awolesi MA, Widmann MD, Sessa WC, Sumpio BE. Cyclic strain increases endothelial nitric-oxide synthase activity. Surgery, 1994, 116:439–445.
41. Li J, Billiar TR, Talanian RV, Kim YM. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Commun, 1997, 240:419–424.
42. Freedman JE, Sauter R, Battinelli EM, Ault K, Knowles C, Huang PL, Loscalzo J. Deficient platelet-derived nitric oxide and enhanced hemostasis in mice lacking the NOSIII gene. Circ Res, 1999, 84:1416–1421.
43. Casas JP, Bautista LE, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation, 2004, 109:1359–1365.
44. Feron O, Smith TW, Michel T, Kelly RA. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem, 1997, 272:17744–17748.
45. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, Marsden PA. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arteriosclerosis Thrombosis Vasc Biol, 1997, 17: 2479–2488.
46. Peng HB, Libby P, Liao JK. Induction and stabilization of I-kappa-B-alpha by nitric-oxide mediates inhibition of Nf-kappa-B. J Biol Chem, 1995, 270:14214–14219.
47. Ju H, Zou R, Venema VJ. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem, 1997, 272: 18522–18525.
48. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol—Regul Integrative Comp Physiol, 2003, 284:R1–R12.
49. Marcun Varda N, Zagradisnik B, Herodez SS, Kokalj Vokac N, Gregoric A. Polymorphisms in four candidate genes in young patients with essential hypertension. Acta Paediatr, 2006, 95(3):353-8.
50. Camp ER, Yang A, Liu W, Fan F, Somcio R, Hicklin DJ, Ellis LM. Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in vivo model of pancreatic cancer. Clin Cancer Res, 2006, 12(8):2628-33.
51. Kaufman DA, Albelda SM, Sun J, Davies PF. Role of lateral cell–cell border location and extracellular/transmembrane domains in PECAM/CD31 mechanosensation. Biochem Biophys Res Commun, 2004, 320:1076–1081.
52. Boo YC, Sorescu GP, Bauer PM, Fulton D, Kemp BE, Harrison DG, Sessa WC, Jo H. Endothelial NO synthase phosphorylated at Ser (635) produces no without requiring intracellular calcium increase. Free Radical Biol Med, 2003, 35:729–741.
53. Boo YC, Jo H. Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases. Am J Physiol—Cell Physiol, 2003, 285:C499–C508.
54. Zhu W, Smart EJ. Myristic acid stimulates endothelial nitric-oxide synthase in a CD36- and an AMP kinase-dependent manner. J Biol Chem, 2005, 280(33):29543-50.
55. Davis ME, Cai H, McCann L, Fukai T, Harrison DG. Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training. Am J Physiol—Heart Circ Physiol, 2003, 284:H1449–H1453.
56. Hambrecht R, Adams V, Erbs S, Linke A, Kr?nkel N, Shu Y, Baither Y, Gielen S, Thiele H, Gummert JF, Mohr FW, Schuler G. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation, 2003, 107:3152–3158.
57. Hoffmann J, Dimmeler S, Haendeler J. Shear stress increases the amount of S-nitrosylated molecules in endothelial cells: important role for signal transduction. FEBS Lett, 2003, 551:153–158.
58. Martin S, Tesse A, Hugel B, Martínez MC, Morel O, Freyssinet JM, Andriantsitohaina R. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation, 2004, 109:1653–1659.
59. Cattaruzza M, Guzik TJ, S?odowski W, Pelvan A, Becker J, Halle M, Buchwald AB, Channon KM, Hecker M. Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease. Circ Res, 2004, 95:841–847.
60. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol—Regul Integrative Comp Physiol, 2003, 285:R277–R297.
61. Rodríguez C, Raposo B, Martínez-González J, Casaní L, Badimon L. Low density lipoproteins downregulate lysyl oxidase in vascular endothelial cells and the arterial wall. Arteriosclerosis Thrombosis Vasc Biol, 2002, 22:1409–1414.
62. Hwang J, Saha A, Boo YC, Sorescu GP, McNally JS, Holland SM, Dikalov S, Giddens DP, Griendling KK, Harrison DG, Jo H. Oscillatory shear stress stimulates endothelial production of O2- from p47(phox)-dependent NAD(P)H oxidases, leading to monocyte adhesion. J Biol Chem, 2003, 278: 47291–47298.
63. Touyz RM, Schiffrin EL. Ang II-stimulated generation of vascular smooth muscle cell reactive oxygen species is increased in human hypertension: role of phospholipase D. Circulation, 1999, 100:479.
64. De Keulenaer GW, Chappell DC, Ishizaka N, Nerem RM, Alexander RW, Griendling KK. Oscillatory and steady laminar shear stress differentially affect human endothelial redox state—role of a superoxide-producing NADH oxidase. Circ Res, 1998, 82:1094–1101.
65. Hwang J, Ing MH, Salazar A, Lassègue B, Griendling K, Navab M, Sevanian A, Hsiai TK. Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression—implication for native LDL oxidation. Circ Res, 2003, 93:1225–1232.
66. Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, TsikasD, Ertl G, Bauersachs J. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007, 56(3):666-74.
67. Hermann C, Zeiher AM, Dimmeler S. Shear stress induced up-regulation of superoxide dismutase inhibits tumor necrosis factor alpha-mediated apoptosis of endothelial cells. Circulation, 1997, 96:2732.
68. Horiuchi M, Tsutsui M, Tasaki H, Morishita T, Suda O, Nakata S, Nihei S, Miyamoto M, Kouzuma R, Okazaki M, Yanagihara N, Adachi T, Nakashima Y. Upregulation of vascular extracellular superoxide dismutase in patients with acute coronary syndromes. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:106–111.
69. Jaimes EA, DeMaster EG, Tian RX, Raij L..Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:1031–1036.
70. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Br?sen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, B?hm M, Meinertz T, Münzel T. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis—evidence for involvement of the renin–angiotensin system. Circulation, 1999, 99:2027–2033.
71. Balletshofer BM, Goebbel S, Rittig K, Enderle M, Schmolzer I, Wascher TC, Ferenc Pap A, Westermeier T, Petzinna D, Matthaei S, Haring HU. Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes--a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial. Exp Clin Endocrinol Diabetes, 2005, 113(6):324-30. .
72. de Nigris F, Lerman A, Ignarro LJ, Williams-Ignarro S, Sica V, Baker AH, Lerman LO, Geng YJ, Napoli C. Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis. Trends Mol Med, 2003, 9:351–359.
73. Iuliano L, Mauriello A, Sbarigia E, Spagnoli LG, Violi F. Vitamin E supplementation in patients with carotid atherosclerosis—reversal of alteredoxidative stress status in plasma but not in plaque. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:136–140.
74. Bonello S, Z?hringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, G?rlach A. Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol, 2007, 27(4):755-61.
75. Weinberg PD. Rate-limiting steps in the development of atherosclerosis: the response – to - influx theory. J Vasc Res, 2004, 41:1–17.
76. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis—site-selective responses to atherosclerotic modulators. Arteriosclerosis Thrombosis Vasc Biol, 2004, 24:12–22.
77. Himburg HA, Grzybowski DM, Hazel AL, LaMack JA, Li XM, Friedman MH. Spatial comparison between wall shear stress measures and porcine arterial endothelial permeability. Am J Physiol—Heart Circ Physiol, 2004, 286: H1916–H1922.
78. Colangelo S, Langille BL, Gotlieb AI. Patterns of distribution characterize the organization of endothelial microfilaments at aortic flow dividers. Cell Tissue Res, 1994, 278:235–242.
79. Noria S, Cowan DB, Gotlieb AI, Langille BL. Transient and steady-state effects of shear stress on endothelial cell adherens junctions. Circ Res, 1999, 85:504–514.
80. Langille BL, Graham JJ, Kim D, Gotlieb AI. Dynamics of shear-induced redistribution of F-actin in endothelial-cells in vivo. Arteriosclerosis Thrombosis 1991, 11:1814–1820.
81. Noria S, Xu F, McCue S, Jones M, Gotlieb AI, Langille BL. Assembly and reorientation of stress fibers drives morphological changes to endothelial cells exposed to shear stress. Am J Pathol, 2004, 164:1211–1223.
82. Dickson BC, Gotlieb AI. Endothelial dysfunction and repair in the pathogenesis of stable and unstable fibroinflammatory atheromas. Can J Cardiol, 2004, 20:16B–23B.
83. Colangelo S, Langille BL, Steiner G, Gotlieb AI. Alterations in endothelial F-actin microfilaments in rabbit aorta in hypercholesterolemia. Arteriosclerosis Thrombosis Vasc Biol, 1998, 18:52–56.
84. Lin T, Zeng L, Liu Y, DeFea K, Schwartz MA, Chien S, Shyy JY. Rho-ROCK-CIMK-Cofilin pathway regulates shear stress activation of sterol regulatory element binding proteins. Circ Res, 2003, 92:1296–1304.