Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix

作     者：Kroon, ME Koolwijk, P van der Vecht, B van Hinsbergh, VWM 

作者机构：TNO PG Gaubius Lab NL-2301 CE Leiden Netherlands Vrije Univ Amsterdam Inst Cardiovasc Res Amsterdam Netherlands 

出 版 物：《BLOOD》 (血液)

年 卷 期：2000年第96卷第8期

页      面：2775-2783页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：受体 细胞表面/生物合成 受体 细胞表面/遗传学 受体 生长因子/拮抗剂和抑制剂 受体 生长因子/免疫学 受体 血管内皮生长因子 受体 玻连蛋白/拮抗剂和抑制剂 受体 玻连蛋白/免疫学 肿瘤坏死因子α/药理学 尿纤溶酶原激活物/生理学 血管内皮生长因子A 血管内皮生长因子受体1 血管内皮生长因子类 

摘      要：Hypoxia stimulates angiogenesis, the formation of new blood vessels. This study evaluates the direct effect of hypoxia (1% oxygen) on the angiogenic response of human microvascular endothelial cells (hMVECs) seeded on top of a 3-dimensional fibrin matrix. hMVECs stimulated with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor (VEGF) together with tumor necrosis factor-alpha (TNF-alpha) formed 2- to 3-fold more tubular structures under hypoxic conditions than in normoxic (20% oxygen) conditions. In both conditions the in-growth of capillary like tubular structures into fibrin required cell-bound urokinase-type plasminogen activator (uPA) and plasmin activities. The hypoxia-induced increase in tube formation was accompanied by a decrease in uPA accumulation in the conditioned medium. This decrease in uPA level was completely abolished by uPA receptor-blocking antibodies. During hypoxic culturing uPA receptor activity and messenger RNA (mRNA) were indeed increased. This increase and, as a consequence, an increase in plasmin formation contribute to the hypoxia-induced stimulation of tube formation. A possible contribution of VEGF-A to the increased formation under hypoxic conditions is unlikely because there was no increased VEGF-A expression detected under hypoxic conditions, and the hypoxia-induced tube formation by FGF-2 and TNF-or was not inhibited by soluble VEGFR-1 (sVEGFR-1), or by antibodies blocking VEGFR-2, Furthermore, although the alpha (v)-integrin subunit was enhanced by hypoxia, blocking antibodies against alpha (v)beta (3)- and alpha (v)beta (5)-integrins had no effect on hypoxia-induced tube formation. Hypoxia increases uPA association and the angiogenic response of human endothelial cells in a fibrin matrix;the increase in the uPA receptor is an important determinant in this process, (C) 2000 by The American Society of Hematology.