UP-REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION INDUCED BY MYOCARDIAL-ISCHEMIA - IMPLICATIONS FOR CORONARY ANGIOGENESIS
UP-REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION INDUCED BY MYOCARDIAL-ISCHEMIA - IMPLICATIONS FOR CORONARY ANGIOGENESIS
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DOI：
10.1093/cvr/28.8.1176
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发表时间：
1994-08-01
影响因子：
10.8
通讯作者：
KESHET, E
中科院分区：
文献类型：
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作者：
BANAI, S;SHWEIKI, D;KESHET, E
目的：冠状动脉侧支循环的形成过程尚不清楚。假设特定的血管生成因子在心肌缺血期间上调，并作为新血管形成的触发因素。然而，这些因素的身份是未知的。血管生成因子血管内皮生长因子（VEGF）已被证明是缺氧诱导的，因此该因子可能介导缺血诱导的心脏血管生成。本研究的目的是研究缺氧诱导的血管内皮生长因子在培养的心肌细胞，以及在正常灌注和缺血的猪心肌。研究方法：（1）体外实验：体外培养大鼠心肌细胞，缺氧2、4 h后，测定心肌细胞VEGF mRNA的稳态水平。(2)体内实验：通过重复2-10分钟的左前降支冠状动脉闭塞，间隔20分钟的再灌注，诱导猪心脏的心肌缺血。在间歇性缺血6小时后取出心脏。从心脏的正常和缺血区提取总RNA，并进行RNA印迹杂交分析。结果：体外实验：缺氧后2-4 h，VEGFmRNA表达明显升高（6-10倍）。体内实验：VEGF表达在心肌缺血区域显著增加（诱导3 - 5倍）。此外，逆转录mRNA的聚合酶链反应扩增显示缺血心肌中多种形式的差异剪接VEGF mRNA的产生增加。结论：心肌中VEGF的产生在体外缺氧和在体内缺血时显著上调。这些结果表明，血管内皮生长因子是一个可能的调解人在自然过程中缺血诱导心肌新生血管。
Objective: The process of coronary collateral development is poorly understood. It is assumed that particular angiogenic factors are upregulated during episodes of myocardial ischaemia and act as a trigger far neovascularisation. However, the identity of these factors is unknown. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be hypoxia inducible, so this factor may mediate ischaemia induced angiogenesis in the heart. The aim of this study was to examine hypoxia inducibility of VEGF in cultured myocardial cells as well as in normally perfused and ischaemic porcine myocardium. Methods: (1) In vitro experiment: cultured rat myocardial cells were subjected to hypoxia, and steady state levels of VEGF mRNA were measured after 2 and 4 h of hypoxia. (2) In vivo experiment: myocardial ischaemia in pigs hearts was induced by repeated 2-10 min left anterior descending coronary artery occlusions, separated by 20 min of reperfusion. Hearts were retrieved after 6 h of intermittent ischaemia. Total RNA was extracted from normal and ischaemic zones of the heart and processed for RNA blot hybridisation analysis. Results: In vitro experiment: as soon as 2-4 h after exposure of cultures to hypoxia, VEGF mRNA levels were significantly raised (6-10-fold). In vivo experiment: VEGF expression was significantly augmented in the ischaemic territory of the myocardium (three- to fivefold induction). Furthermore, polymerase chain reaction amplification of the reverse transcribed mRNA showed increased production of multiple forms of differentially spliced VEGF mRNA in the ischaemic myocardium. Conclusions: VEGF production in the myocardium is significantly upregulated by hypoxia in vitro and by ischaemia in vivo. These results suggest that VEGF is a likely mediator in the natural process of ischaemia induced myocardial neovascularisation.