生长因子与心肌缺血及血管再生关系的研究进展
作者：卫洪超 朱洪生
单位：(上海第二医科大学附属仁济医院胸心外科 上海 200025)
关键词：
心血管病学进展000216文章编号：1004-3934(2000)02-0111-02 分类号：Q516；R541.4
文献标识码：A
Advance in Research of the Relation Between Growth Factor and Myocardium Ischemia and Vessel Growth
WEI Hong-chao,ZHU Hong-sheng
(Department of Thoracic Cardiac Surgery,The Affiliated Renji Hospital of Shanghai Second Medical University,Shanghai,200025)▲
, http://www.100md.com
基础与临床研究均表明，冠状动脉粥样硬化，必然导致程度不同的心肌缺血。在冠心病自然病程中，心肌能够逐渐建立起自身的侧枝循环，靠部分代偿性血管再生，适应或抵御心肌局部的缺血缺氧[1]。心肌缺血时的血管再生，现在认为，是由生长因子引起的血管新生。这些生长因子绝大部分是肽类生长因子家族的成员[2]。临床研究证明，靠再生新的血管以适应缺血变化的过程非常缓慢，且一般情况下，只能部分代偿冠状动脉阻塞引起的心肌缺血。因此，在血管成形术、冠状动脉旁路术不能奏效的时候，人为的增加心肌局部生长因子的浓度，对缓解以致解除心肌缺血有潜在的可行性。这种人工控制的血管再生的方法曾一度叫做“治疗性血管再生”，或“分子搭桥术”。有人在犬的心肌[3，4]、猪的心肌[5，6]、家兔后肢肌缺血模型[7-9]、大鼠的心肌及后肢肌缺血等模型[10，11]中，应用生长因子进行了实验性治疗。结果表明，缺血的骨骼肌可建立大量的侧枝循环；在心肌中，微血管密度的增加，会引起冠脉血流量的增加，梗塞面积的显著缩小及心功能的明显改善。
, 百拇医药
一种能够引起血管再生的生长因子是血管内皮生长因子(vascular endothelial growth factor;VEGF)，它也可以使血管的通透性增加。VEGF是内皮细胞特异性的生长因子，在缺血组织及肿瘤组织中均有高度特异性。VEGF有五型，这是因为同一基因可产生五种类型的mRNA[12]。目前，VEGF-B[13]、VEGF-C[14]的基因已经克隆出来。但是它们在血管再生时对血管内皮细胞功能的调节机制尚未明了。现在知道。在机体缺氧或缺血条件下，VEFD-A表达上调[15，16]，且这种作用发生在转录后水平[17]。研究发现[18]，缺氧及缺血条件下，VEGF的受体KDR/Flt-1也上调。实验表明，这种作用不但发生在转录水平，而且在翻译水平及靶器官水平，VEGF的作用均有变化。Flt-1[19]的确切功能尚不清楚，但它可以诱导内皮细胞及单核细胞表达大量的组织因子。同时，Flt-1与单核细胞的趋化性有关[20]。VEGF应用于缺血肢体及缺血心肌有很强的再血管化作用。表现为组织灌注增加，肌肉的舒缩力显著增强[21]。另外，在血管成形术后，VEGF还可以促使血管内膜的再生及保护内膜不至于朔形[22，23]。除了KDR及Flt-1，另外两种受体，Tie-1及Tie-2在内皮细胞中也有特异性表达。这种表达在胚胎心血管系统的发育过程中起关键作用[24]。但它们在代偿性血管再生中的作用尚不清楚。
, http://www.100md.com
基本的成纤维细胞生长因子(bFGF)直接作用于平滑肌细胞及血管内皮细胞，但无细胞特异性[25]。bFGF是高效能的血管再生刺激因子，在不同的动物模型中都可引起血管再生[3-11]。但另有一些实验却得出相反的结果。仔细分析知道，这些实验的原始数据，如药物的剂量、用药的方式均不相同。因此，应用生长因子的时间点、药物剂量及用药方式的不同可能是产生两者差别的原因。bFGF除能使血管再生外，对心血管系统也有其它作用。在犬的冠状动脉阻塞后再通模型中，于冠脉内应用bFGF，术后第七天梗塞面积明显缩小，但没有发现新生血管[25]。近年来有人[26]用成纤维细胞生长因子(FGF)家族的另一成员FGF-5，介导以腺病毒载体进行FGF-5基因转移，用于治疗猪的心肌缺血，ECG等心功能指标测定结果显示有积极效果。但是，毛细血管的数量及密度与自身缺血前对照，统计学上没有显著差异。离体实验研究表明，VEGF及bFGF合并应用方可发挥最大的效能。另外，bFGF使VEGF表达上调[27]。然而，bFGF可以促进动脉粥样硬化的形成，血管内膜过度增厚[25，28]。这种特点可能会限制bFGF与VEGF的合并应用。同样，对于血小板源性生长因子(PDGF)来说，尤其是PDGF-BB对侧枝循环及血管间吻合支的形成有很强的刺激作用[28]。研究表明，血管内皮细胞可以表达PDGF的受体，介导PDGF引起血管再生。PDGF-BB可使bFGF、FGFR-1及VEGF上调。因此可以说PDGF，是血管再生的间接诱导剂[29]。
, 百拇医药
缺血心肌或肢体中侧枝循环的形成，对心肌或骨骼肌收缩功能的恢复无疑是有利的。但在动脉粥样硬化斑块中，新生血管的增加是斑块破裂的原因之一[30]。在动脉粥样硬化斑块中，哪种物质引起血管再生，尚不清楚。动脉壁平滑肌细胞可以产生VEGF，所以VEGF可能参与粥样斑块的形成与发展。同样，FGF家族的另一位成员FGF-1与动脉粥样硬化斑块的进展亦有密切关系。FGF-1在血管壁中的过度表达会引起新毛细血管的形成。研究表明，斑块内血管的再生与新内膜的过度形成有关。斑块内过多的血液灌注势必会加速动脉粥样硬化进展[30]。因此，抑制粥样硬化斑块内的血管再生，对缓解动脉粥样硬化的严重程度，防治并发症有积极意义。■
参考文献：
[1]Waltenberg J.Modulation of growth factor:Implication for the treatment of cardiovascular diseases[J].Circulation,1997,96(11):4083-4094
, http://www.100md.com
[2]Schaper W,Ito WD.Molecular mechanism of coronary collateral vessel growth[J].Cir Res,1996,79:911-919
[3]Yanagisawa-Miwa A,Uchida Y,Nakamura F,et al.Salvage of infaracted myocardium by angiogenic action of basic fibroblast growth factor[J].Science,1992,257:1401-1403
[4]Baffour R,Berman J,Gerb JI,et al.Enhanced angiogenesis and growth of colloterals by in vivo administration of recombinant basic fibrooblast growth factor in a rabbit model of acute lower limb ischema,dose-repnse effect of basic fibrblast growth factor[J].J Vasc Surg.1992,16:181-191
, http://www.100md.com
[5]Battler A,Schinowitz M,Bor A,et al.Intracoronary injection of basic fibroblast growth factor enchances angiogenesis in infaracted swine myocardium[J].J Am Cell Cardiol,1993,22:2001-2006
[6]Harada K,Grossman W,Friedman M,et al.Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts[J].J Clin Invest,1994,49:623-630
[7]Uchida Y,Yanagisawa-Miwa A,Ikuta M,et al.Angiogenic therapy of acute myocardial infarction(AMI)by intrapericardial injection of basic fibroblast growth factor (bFGF) and haparan sulfate (HS):an experimental study[J].Circulation,1994,90(suppll):I-296(Abstract)
, http://www.100md.com
[8]Unger EF,Bomai S,Shon M,et al.Basic fibroblast growth factor enhances myocardial collateral flow in a canine model[J].Am J Physiol,1994,35:H1588-H1595
[9]Lazarous DF,Scheinowitz M,Shou M,et al.Effect of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart[J].Circulation,1995,91:145-153
[10]Barrios V,Cuevas B,Carceller F,et al.Angiogenesis in the rat heart induced by local delivery of basic fibroblast growth factor[J].Eur Heat J,1995,16(suppl):171
, http://www.100md.com
[11]Yang HT,Deschenes MR,Ogilvi RW,et al.Basic fibroblast growth factor increases collateral blood flow in rats with femoral arterial ligation[J].Circ Res.1996,79:62-69
[12]Thomas KA.Vascular endothelial growth factor a potent and selective angiogenic agent[J].J Biol Chem,1996,271:603-606
[13]Olofsso B,Pajusola K,Kaipamen A,et al.Vascular endothelial growth factor-B.a novel growth factor for endothelial cells[J].Proc Natl Acad Sci USA,1996,93:2576-2581
, 百拇医药
[14]Joukov V,Pajusola K,Kaipainen A,et al.A novel vascular endothelail growth factor VEGF-C,is a ligand for the Flt-4(VEFDR-3)and KDR(VEGF-2)receptor tyrosine kinases[J].EMBO J,1996,15:290-298
[15]Shweiki D,Itin J,Soffer D,et al.Vascular endothelial growth factor induced by hyposia may mediate hypoxia-initiated angiogenesis[J].Nature,1992,359:834-845
[16]Banai S,Shweiki D,Pinson A,et al.Upregulation of vascular endothelial growth factor expression induced by myocardium ischaemia:implication for coronary angiogenesis[J].Cardiovasc Res,1994,28:1176-1179
, http://www.100md.com
[17]Ikeda E,Achen MG,Breier G,et al.Hypoxia induced trancriptional activation and increased mRNA stability of vascular endothelial growth fctor in C6 glioma cells[J].J Biol Chem,1995,270:19761-19766
[18]Waltenberger J,Claesson-Welsh L,Siegbahn A,et al.Different signal transduction properties of KDR and Flt-l two receptors for vascular endothelial growth factr[J].J Biol Chem,1994,269:26988-26995
[19]Pepper MS,Ferrara N,Orei L,et al.Potent synergism between vascular endotheial growth factror and basic fibroblast growth factor in the induction of angiogenesis in witro[J].Biochem Biophys Res Commum,1992,189:824-831
, http://www.100md.com
[20]Clanss M,Weich H,Breier G,et al.The vascular endothelial growth facotr Fltl-l mediates biological actovities:implications for a functinal role of placenta gowth factor in myocyte activaton and chemotaxis[J].J Biol Chem.1996,271:17629-17634
[21]Engler DA.Use of vascular endothelial growth factor for therapeutic angiogenesis[J].Circulation,1996,94:1496-1498
[22]Callow AD,Choi ET,Trachtenberg JD,et al.Vascular permeability factor accelerates endothelial growth following balloon angioplasty[J].Growth Factors,1994,10:223-228
, 百拇医药
[23]Asahara T,Banters C,Pastore C,et al.Local delivery of vascular endothelial growth factor acclerates reendothelialization and attenuates intimal hyperpplasia in ballon-injured rat carotid atrery[J].Circulation,1995,91:2793-2801
[24]Merenmies J,Parad LF,Henkenmeyer M.Receptor tyrosine kinase signaling in vascular development[J].Cell Growth Differ,1997,8:3-10
[25]Lindner V,Reidy MA.Expression of basic fibroblast growth factor and its receptor by smooth muscle cells and endothelium in injured rat arteries:an en face study[J].Circ Res,1993,73:589-595
, 百拇医药
[26]Giord FJ,Ping P,Mckirnan MD,et al.Intracoronary gene transfer of fibroblast growth factor-5 increases bolld flow and contractile functon in an ischemic region of the heart[J].Nat Med,1996,2:534-539
[27]Stavri GT,Zachhary IC,Baskerville PA,et al.Basic fibroblast growth factor upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells[J].Circulation,1995,92:11-14
[28]Linder V,Laappi DA,Baird A,et al.Role of basic fibroblast growth factor in vascular lesion formation[J].Circ Res,1991,68:106-113
, 百拇医药
[29]Brown DM,Hong SP,Farrel CL,et al.Platelete-derived growth factor-BB induced function vascular anistoses in vivo[J].Proc Natl Acad Sci USA.1995,92:5920-5924
[30]OBrain ER,Garvin,MR,Dev R,et al.Angiogenesis in human coronary atherosclerotic ploques[J]. Am J Pathol,1994,145:833-894
收稿日期：1999-01-20, 百拇医药
单位：(上海第二医科大学附属仁济医院胸心外科 上海 200025)
关键词：
心血管病学进展000216文章编号：1004-3934(2000)02-0111-02 分类号：Q516；R541.4
文献标识码：A
Advance in Research of the Relation Between Growth Factor and Myocardium Ischemia and Vessel Growth
WEI Hong-chao,ZHU Hong-sheng
(Department of Thoracic Cardiac Surgery,The Affiliated Renji Hospital of Shanghai Second Medical University,Shanghai,200025)▲
, http://www.100md.com
基础与临床研究均表明，冠状动脉粥样硬化，必然导致程度不同的心肌缺血。在冠心病自然病程中，心肌能够逐渐建立起自身的侧枝循环，靠部分代偿性血管再生，适应或抵御心肌局部的缺血缺氧[1]。心肌缺血时的血管再生，现在认为，是由生长因子引起的血管新生。这些生长因子绝大部分是肽类生长因子家族的成员[2]。临床研究证明，靠再生新的血管以适应缺血变化的过程非常缓慢，且一般情况下，只能部分代偿冠状动脉阻塞引起的心肌缺血。因此，在血管成形术、冠状动脉旁路术不能奏效的时候，人为的增加心肌局部生长因子的浓度，对缓解以致解除心肌缺血有潜在的可行性。这种人工控制的血管再生的方法曾一度叫做“治疗性血管再生”，或“分子搭桥术”。有人在犬的心肌[3，4]、猪的心肌[5，6]、家兔后肢肌缺血模型[7-9]、大鼠的心肌及后肢肌缺血等模型[10，11]中，应用生长因子进行了实验性治疗。结果表明，缺血的骨骼肌可建立大量的侧枝循环；在心肌中，微血管密度的增加，会引起冠脉血流量的增加，梗塞面积的显著缩小及心功能的明显改善。
, 百拇医药
一种能够引起血管再生的生长因子是血管内皮生长因子(vascular endothelial growth factor;VEGF)，它也可以使血管的通透性增加。VEGF是内皮细胞特异性的生长因子，在缺血组织及肿瘤组织中均有高度特异性。VEGF有五型，这是因为同一基因可产生五种类型的mRNA[12]。目前，VEGF-B[13]、VEGF-C[14]的基因已经克隆出来。但是它们在血管再生时对血管内皮细胞功能的调节机制尚未明了。现在知道。在机体缺氧或缺血条件下，VEFD-A表达上调[15，16]，且这种作用发生在转录后水平[17]。研究发现[18]，缺氧及缺血条件下，VEGF的受体KDR/Flt-1也上调。实验表明，这种作用不但发生在转录水平，而且在翻译水平及靶器官水平，VEGF的作用均有变化。Flt-1[19]的确切功能尚不清楚，但它可以诱导内皮细胞及单核细胞表达大量的组织因子。同时，Flt-1与单核细胞的趋化性有关[20]。VEGF应用于缺血肢体及缺血心肌有很强的再血管化作用。表现为组织灌注增加，肌肉的舒缩力显著增强[21]。另外，在血管成形术后，VEGF还可以促使血管内膜的再生及保护内膜不至于朔形[22，23]。除了KDR及Flt-1，另外两种受体，Tie-1及Tie-2在内皮细胞中也有特异性表达。这种表达在胚胎心血管系统的发育过程中起关键作用[24]。但它们在代偿性血管再生中的作用尚不清楚。
, http://www.100md.com
基本的成纤维细胞生长因子(bFGF)直接作用于平滑肌细胞及血管内皮细胞，但无细胞特异性[25]。bFGF是高效能的血管再生刺激因子，在不同的动物模型中都可引起血管再生[3-11]。但另有一些实验却得出相反的结果。仔细分析知道，这些实验的原始数据，如药物的剂量、用药的方式均不相同。因此，应用生长因子的时间点、药物剂量及用药方式的不同可能是产生两者差别的原因。bFGF除能使血管再生外，对心血管系统也有其它作用。在犬的冠状动脉阻塞后再通模型中，于冠脉内应用bFGF，术后第七天梗塞面积明显缩小，但没有发现新生血管[25]。近年来有人[26]用成纤维细胞生长因子(FGF)家族的另一成员FGF-5，介导以腺病毒载体进行FGF-5基因转移，用于治疗猪的心肌缺血，ECG等心功能指标测定结果显示有积极效果。但是，毛细血管的数量及密度与自身缺血前对照，统计学上没有显著差异。离体实验研究表明，VEGF及bFGF合并应用方可发挥最大的效能。另外，bFGF使VEGF表达上调[27]。然而，bFGF可以促进动脉粥样硬化的形成，血管内膜过度增厚[25，28]。这种特点可能会限制bFGF与VEGF的合并应用。同样，对于血小板源性生长因子(PDGF)来说，尤其是PDGF-BB对侧枝循环及血管间吻合支的形成有很强的刺激作用[28]。研究表明，血管内皮细胞可以表达PDGF的受体，介导PDGF引起血管再生。PDGF-BB可使bFGF、FGFR-1及VEGF上调。因此可以说PDGF，是血管再生的间接诱导剂[29]。
, 百拇医药
缺血心肌或肢体中侧枝循环的形成，对心肌或骨骼肌收缩功能的恢复无疑是有利的。但在动脉粥样硬化斑块中，新生血管的增加是斑块破裂的原因之一[30]。在动脉粥样硬化斑块中，哪种物质引起血管再生，尚不清楚。动脉壁平滑肌细胞可以产生VEGF，所以VEGF可能参与粥样斑块的形成与发展。同样，FGF家族的另一位成员FGF-1与动脉粥样硬化斑块的进展亦有密切关系。FGF-1在血管壁中的过度表达会引起新毛细血管的形成。研究表明，斑块内血管的再生与新内膜的过度形成有关。斑块内过多的血液灌注势必会加速动脉粥样硬化进展[30]。因此，抑制粥样硬化斑块内的血管再生，对缓解动脉粥样硬化的严重程度，防治并发症有积极意义。■
参考文献：
[1]Waltenberg J.Modulation of growth factor:Implication for the treatment of cardiovascular diseases[J].Circulation,1997,96(11):4083-4094
, http://www.100md.com
[2]Schaper W,Ito WD.Molecular mechanism of coronary collateral vessel growth[J].Cir Res,1996,79:911-919
[3]Yanagisawa-Miwa A,Uchida Y,Nakamura F,et al.Salvage of infaracted myocardium by angiogenic action of basic fibroblast growth factor[J].Science,1992,257:1401-1403
[4]Baffour R,Berman J,Gerb JI,et al.Enhanced angiogenesis and growth of colloterals by in vivo administration of recombinant basic fibrooblast growth factor in a rabbit model of acute lower limb ischema,dose-repnse effect of basic fibrblast growth factor[J].J Vasc Surg.1992,16:181-191
, http://www.100md.com
[5]Battler A,Schinowitz M,Bor A,et al.Intracoronary injection of basic fibroblast growth factor enchances angiogenesis in infaracted swine myocardium[J].J Am Cell Cardiol,1993,22:2001-2006
[6]Harada K,Grossman W,Friedman M,et al.Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts[J].J Clin Invest,1994,49:623-630
[7]Uchida Y,Yanagisawa-Miwa A,Ikuta M,et al.Angiogenic therapy of acute myocardial infarction(AMI)by intrapericardial injection of basic fibroblast growth factor (bFGF) and haparan sulfate (HS):an experimental study[J].Circulation,1994,90(suppll):I-296(Abstract)
, http://www.100md.com
[8]Unger EF,Bomai S,Shon M,et al.Basic fibroblast growth factor enhances myocardial collateral flow in a canine model[J].Am J Physiol,1994,35:H1588-H1595
[9]Lazarous DF,Scheinowitz M,Shou M,et al.Effect of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart[J].Circulation,1995,91:145-153
[10]Barrios V,Cuevas B,Carceller F,et al.Angiogenesis in the rat heart induced by local delivery of basic fibroblast growth factor[J].Eur Heat J,1995,16(suppl):171
, http://www.100md.com
[11]Yang HT,Deschenes MR,Ogilvi RW,et al.Basic fibroblast growth factor increases collateral blood flow in rats with femoral arterial ligation[J].Circ Res.1996,79:62-69
[12]Thomas KA.Vascular endothelial growth factor a potent and selective angiogenic agent[J].J Biol Chem,1996,271:603-606
[13]Olofsso B,Pajusola K,Kaipamen A,et al.Vascular endothelial growth factor-B.a novel growth factor for endothelial cells[J].Proc Natl Acad Sci USA,1996,93:2576-2581
, 百拇医药
[14]Joukov V,Pajusola K,Kaipainen A,et al.A novel vascular endothelail growth factor VEGF-C,is a ligand for the Flt-4(VEFDR-3)and KDR(VEGF-2)receptor tyrosine kinases[J].EMBO J,1996,15:290-298
[15]Shweiki D,Itin J,Soffer D,et al.Vascular endothelial growth factor induced by hyposia may mediate hypoxia-initiated angiogenesis[J].Nature,1992,359:834-845
[16]Banai S,Shweiki D,Pinson A,et al.Upregulation of vascular endothelial growth factor expression induced by myocardium ischaemia:implication for coronary angiogenesis[J].Cardiovasc Res,1994,28:1176-1179
, http://www.100md.com
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收稿日期：1999-01-20, 百拇医药