Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit
Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit
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DOI：
10.1161/hh2101.098613
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发表时间：
2001-10-26
影响因子：
20.1
通讯作者：
Schaper, W
中科院分区：
文献类型：
--
作者：
Deindl, E;Buschmann, I;Schaper, W
血管内皮生长因子（VEGF）在血管生成中起重要作用。然而，它在侧支动脉生长（动脉发生）中的地位仍有争议。在本研究中，我们分析了兔股动脉闭塞后副动脉生长模型中VEGF及其受体Flk-1和Flt-1的表达。缺氧是VEGF表达最重要的刺激因素。因此，我们还研究了不同的缺氧诱导基因（HIF-1 α, LDH A）的表达水平，并确定了指示缺血的代谢中间体（ATP，磷酸肌酸及其分解产物）。我们发现动脉生成与VEGF或上述缺氧诱导基因的表达增加无关。此外，高能磷酸盐及其分解产物完全在正常范围内。尽管没有VEGF及其受体的表达增加，侧支血管的直径增加了10倍。输注趋化单核细胞趋化蛋白-1可以加快侧枝发育的速度，但输注高于30倍浓度的VEGF则不能。根据这些数据，我们得出结论，在非缺血条件下，血管生成既与VEGF水平升高无关，也不受VEGF水平升高的诱导，VEGF不是体内诱导动脉生成的天然药物。
Vascular endothelial growth factor (VEGF) is known to play an important role in angiogenesis. Its place in collateral artery growth (arteriogenesis), however, is still debated. In the present study, we analyzed the expression of VEGF and its receptors (Flk-1 and Flt-1) in a rabbit model of collateral artery growth after femoral artery occlusion. Hypoxia presents the most important stimulus for VEGF expression. We therefore also investigated the expression level of distinct hypoxia-inducible genes (HIF-1 alpha, LDH A) and determined metabolic intermediates indicative for ischemia (ATP, creatine phosphate, and their catabolites). We found that arteriogenesis was not associated with an increased expression of VEGF or the mentioned hypoxia-inducible genes. Furthermore, the high-energy phosphates and their catabolites were entirely within normal limits. Despite the absence of an increased expression of VEGF and its receptors, collateral vessels increased their diameter by a factor of 10. The speed of collateral development could be increased by infusion of the chemoattractant monocyte chemotactic protein-1 but not by infusion of a 30 times higher concentration of VEGF. From these data, we conclude that under nonischemic conditions, arteriogenesis is neither associated with nor inducible by increased levels of VEGF and that VEGF is not a natural agent to induce arteriogenesis in vivo.