VEGF-induced blood flow increase causes vascular hyper-permeability in vivo.
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.
['Ashina|Kohei|K|', 'Tsubosaka|Yoshiki|Y|', 'Kobayashi|Koji|K|', 'Omori|Keisuke|K|', 'Murata|Takahisa|T|']
D000818:Animals D001775:Blood Circulation D002199:Capillary Permeability D004730:Endothelium, Vascular D051379:Mice D052250:Nitric Oxide Synthase Type III D019869:Phosphatidylinositol 3-Kinases D010766:Phosphorylation D015398:Signal Transduction D042461:Vascular Endothelial Growth Factor A
Blood flow VEGF Vascular permeability Endothelial barrier Nitric oxide