VEGF-induced blood flow increase causes vascular hyper-permeability in vivo
VEGF-induced blood flow increase causes vascular hyper-permeability in vivo
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DOI：
10.1016/j.bbrc.2015.07.014
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发表时间：
2015-08-21
影响因子：
3.1
通讯作者：
Murata, Takahisa
中科院分区：
文献类型：
--
作者：
Ashina, Kohei;Tsubosaka, Yoshiki;Murata, Takahisa
已知VEGF可引起血管渗漏，但其在体内的具体机制尚不清楚。在这里，我们研究了vegf诱导血管高通透性的机制，重点研究了血管通透性的两个主要调节因子：血流和内皮屏障功能。VEGF引起小鼠耳血管高通透性和组织肿胀，而VEGF受体-2阻断可消除这一现象。活体显像显示VEGF扩张耳动脉而非静脉，激光多普勒测速显示VEGF随动脉扩张迅速增加组织血流量。全贴壁免疫染色显示，VEGF使内皮型一氧化氮合酶（eNOS）在Ser1177位点磷酸化，破坏了小鼠耳皮肤内皮细胞边界周围血管内皮-钙粘蛋白（VE-cadherin）的排列，提示内皮型一氧化氮（NO）的产生和屏障破坏。一氧化氮合成抑制剂L-NAME和血管收缩剂苯肾上腺素可以消除vegf诱导的所有反应，包括血流量增加、染料泄漏和组织肿胀。然而，这两种处理并没有改变VEGF诱导的ve -cadherin的细胞内定位。这些观察结果强调了血管扩张的重要性，随后的血流量增加，以及内皮屏障破坏在vegf诱导的血管高渗透性机制中的重要性。(C) 2015爱思唯尔公司版权所有。
VEGF is known to cause vascular leak, its detailed mechanisms in vivo remain unclear. Here, we investigated the mechanisms underlying VEGF-induced vascular hyper-permeability focusing on two major regulators of vascular permeability: blood flow and endothelial barrier function. Administration of VEGF caused vascular hyper-permeability and tissue swelling in mouse ears, which were abolished by VEGF receptor-2 blockade. Intravital imaging showed that VEGF dilated ear arteries but not veins, and laser Doppler velocimetry showed that VEGF quickly increased tissue blood flow along with arterial dilation. Whole-mount immunostaining showed that VEGF phosphorylated endothelial nitric oxide synthase (eNOS) at residue Ser1177 and disrupted the alignment of vascular endothelial-cadherin (VE-cadherin) around the endothelial cell borders in mouse ear skin, indicating endothelial nitric oxide (NO) production and barrier disruption. Administration of the nitric oxide synthesis inhibitor, L-NAME, as well as the vasoconstrictor phenylephrine, abolished all VEGF-induced responses, including blood flow increase, dye leakage, and tissue swelling. However, these two treatments did not alter the intracellular localization of VE-cadherin-induced by VEGF. These observations underscore the importance of vascular dilation and, subsequent increase in blood flow, as well as, endothelial barrier disruption in the mechanisms of VEGF-induced vascular hyper-permeability. (C) 2015 Elsevier Inc. All rights reserved.