Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor
Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor
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DOI：
10.1161/01.atv.0000245821.77155.c3
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发表时间：
2006-12
期刊：
影响因子：
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通讯作者：
H. Sano;K. Hosokawa;H. Kidoya;N. Takakura
中科院分区：
文献类型：
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作者：
H. Sano;K. Hosokawa;H. Kidoya;N. Takakura
血管的渗透性对组织的稳态是必不可少的。然而，无序的高通透性导致疾病的进展。血管内皮生长因子-A（VEGF）是血管渗漏的关键调节因子，并且已经报道VEGF介导的高通透性被血管生成素-1（Ang 1）抑制。我们发现，血管紧张素转换酶（ACE）下调内皮细胞的Ang 1。ACE将血管紧张素I转化为血管紧张素II（AII）。在这里，我们研究了VEGF和AII相对于血管通透性的关系。方法和结果：我们发现给予AII 1型受体（AT 1 R）阻断剂（ARB）的小鼠VEGF介导的血管通透性增高受到抑制; AT 1 R缺陷小鼠也观察到这种效应。在这个系统中，我们发现ARB抑制VEGF诱导的间隙形成。此外，我们确定，血管内皮生长因子过度表达诱导的血管性水肿显着减少ARB治疗的缺血小鼠。结论：由于ARB抑制VEGF诱导的血管通透性增高，我们认为ARB可用于减少VEGF治疗性血管生成中水肿的风险。
Objective—Permeability of blood vessels is essential for tissue homeostasis. However, disorganized hyperpermeability leads to progression of diseases. Vascular endothelial growth factor-A (VEGF) is a key regulator for leakiness of blood vessels and it has been reported that VEGF-mediated hyperpermeability was suppressed by angiopoietin-1 (Ang1). We found that Angiotensin-converting enzyme (ACE) was downregulated in endothelial cells by Ang1. ACE converts angiotensin I to angiotensin II (AII). Here, we studied the relationship between VEGF and AII relative to vascular permeability. Methods and Results—We showed that VEGF-mediated vascular hyperpermeability was suppressed in mice given AII type 1 receptor (AT1R) blocker (ARB); the effect was also seen in AT1R-deficient mice. In this system, we found that ARB inhibited VEGF-induced gap formation. Furthermore, we ascertained that angioedema induced by overexpression of VEGF decreased noticeably in ARB-treated ischemic mice. Conclusions—Because ARB suppressed VEGF-induced vascular hyperpermeability, we propose that ARB may be used to minimize the risk of edema in therapeutic angiogenesis using VEGF.