血管内皮生长因子受体2 (KDR)是血管内皮生长因子降压作用的主要调节因子

Bing Li, A. Ogasawara, Renhui Yang, Wei Wei, G. He, T. F. Zioncheck, S. Bunting, A. D. de Vos, Hongkui Jin
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引用次数: 120

摘要

血管内皮生长因子(VEGF)发挥血管舒张诱导的低血压是缺血性疾病治疗的主要副作用。VEGF有2种受体酪氨酸激酶,KDR和Flt-1。对于哪种受体介导vegf诱导的低血压知之甚少。为了阐明每种受体在介导低血压中的作用,kdr选择性和flt -1选择性突变体被用于体外和体内研究。kdr选择性突变体诱导血管内皮细胞增殖与VEGF相当,而Flt-1选择性突变体对增殖没有影响。静脉注射kdr选择性突变体、flt选择性突变体或VEGF导致有意识大鼠平均动脉压的剂量相关降低。kdr -选择性突变体的降压效果显著低于VEGF (P <0.01),而高于flt -选择性突变体(P <0.01)。同样,VEGF和kdr -选择性突变体诱导的血管舒张作用强于flt -选择性突变体或仅结合Flt-1的胎盘生长因子(P <0.01),且kdr -选择性突变体的血管舒张作用在低浓度下无显著差异,而在高浓度下则小于VEGF。结果表明,VEGF的血管扩张和降压作用可能涉及两种受体,但KDR是介导这种作用的主要受体。由于kdr选择性突变体诱导的增殖和血管生成与VEGF相似,但与低血压降低36%相关,数据表明kdr选择性突变体可能代表缺血性疾病的替代治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
KDR (VEGF Receptor 2) Is the Major Mediator for the Hypotensive Effect of VEGF
Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1–selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1– selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P <0.01) but was greater than that to Flt-selective mutant (P <0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P <0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.
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