P5398Vasohibin-2 exacerbates development of angiotensin II-induced thoracic aortic aneurysms independent of VEGF

Background: Chronic angiotensin II (AngII) infusion promotes both thoracic (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Previous studies showed that vascular endothelial growth factor (VEGF) enhanced AngII-induced AAA formation, and VEGF significantly increased Angll-induced AAA diameter in hypercholesterolemic mice. Meanwhile, vasohibin-1 (VASH1) is induced by VEGF and inhibits angiogenesis under various pathologic conditions. In contrast, a VASH1 homolog, vasohibin-2 (VASH2) promotes angiogenesis at the sprouting front of neovascularization. Therefore, we hypothesized that exogenous VASH2 influences AngII-induced TAAs in normocholesterolemic mice. Purpose: The purpose of this study was to examine whether VASH2 influenced AngII-induced TAAs. Methods: Male C57BL/6J mice (10-week-old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5x109 vp/100 μvia tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of either AngII (1,000 ng/kg/min) or saline by mini osmotic pumps was started for 3 weeks. Consequently, mice were divided into 4 groups: AngII + Ad VASH2 (n=22), AngII + Ad LacZ (n=21), saline + Ad VASH2 (n=10), saline + Ad LacZ (n=8). Next, in order to examine whether VASH2 affected TAAs via VEGF regulation, bevacizumab was intraperitoneally administrated into mice; AngII + Ad VASH2 + saline (n=15), AngII + Ad VASH2 + bevacizumab (n=15). TAAs were evaluated in all mice by en face method. Third, human aortic smooth muscle cells (hSMCs) were infected with Ad VASH2 or Ad LacZ, stimulated with or without AngII to evaluate further mechanism.