Elevated vascular endothelial growth factor receptor-2 abundance contributes to increased angiogenesis in vascular endothelial growth factor receptor-1-deficient mice.
Elevated vascular endothelial growth factor receptor-2 abundance contributes to increased angiogenesis in vascular endothelial growth factor receptor-1-deficient mice.
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DOI：
10.1161/circulationaha.112.091603
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发表时间：
2012-08-07
期刊：
影响因子：
37.8
通讯作者：
Fong GH
中科院分区：
文献类型：
--
作者：
Ho VC;Duan LJ;Cronin C;Liang BT;Fong GH
血管内皮生长因子受体-1（Vascular endothelial growth factor receptor-1，VEGFR-1/Flt-1）是一个潜在的心血管疾病治疗靶点，但其在血管生成中的作用仍存在争议。虽然生殖系Vegfr-1−/−胚胎死于与过度内皮分化相关的异常血管发育，但仅缺乏激酶结构域的小鼠显然是健康的。我们进行了Cre-loxP介导的基因敲除，以消除所有已知的VEGFR-1功能域的表达在新生儿和成年小鼠，并分析了发育，病理生理和分子后果。血管内皮生长因子受体-1的缺陷促进尖端细胞的形成和内皮细胞（EC）的增殖，并促进血管生成的血管成熟和灌注适当。血管通透性在基础水平是正常的，但在高剂量的外源性VEGF-A的反应升高。在梗死后缺血性心肌病模型中，VEGFR-1缺陷支持强大的血管生成并保护心肌梗死。VEGFR-1基因敲除导致VEGFR-2在蛋白水平上大量积累，瞬时增加VEGFR-2酪氨酸磷酸化，并增强Akt和ERK的丝氨酸磷酸化。有趣的是，增加的血管生成，尖端细胞形成，血管通透性，VEGFR-2积累和Akt磷酸化可以通过以下一种或多种操作部分挽救或抑制，包括注射VEGFR-2选择性抑制剂SU 1498，抗VEGF-A，或将Vegfr-2+/−杂合性引入Vegfr-1体细胞敲除小鼠。VEGFR-2丰度在蛋白水平上的上调部分有助于VEGFR-1缺陷小鼠中血管生成的增加。
Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. While germline Vegfr-1−/− embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain are apparently healthy. We carried out Cre-loxP mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice, and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell (EC) proliferation, and facilitated angiogenesis of blood vessels which matured and perfused properly. Vascular permeability was normal at the basal level, but elevated in response to high doses of exogenous VEGF-A. In the post-infarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of Vegfr-2+/− heterozygosity into Vegfr-1 somatic knockout mice. Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1 deficient mice.