Vanderslice P, Munsch C L, Rachal E, Erichsen D, Sughrue K M, Truong A N, Wygant J N, McIntyre B W, Eskin S G, Tilton R G, Polverini P J
Department of Immunology, Texas Biotechnology Corporation, Houston, TX, USA.
Angiogenesis. 1998;2(3):265-75. doi: 10.1023/a:1009296700991.
Tumor necrosis factor-alpha (TNF-alpha) and fibroblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF- alpha, but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells. The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that monoclonal antibodies directed against VCAM-1 or its alpha4 integrin counter- receptor inhibited TNF-alpha-induced endothelial cell migration in vitro. Angiogenesis induced in vivo in rat corneas by TNF-alpha was inhibited by a neutralizing antibody directed against the rat alpha4 integrin subunit. A peptide antagonist of the a4 integrins blocked TNF-alpha-induced endothelial cell migration in vitro and angiogenesis in rat corneas in vivo. No inhibition by the antibodies or peptide antagonist was observed either in vitro or in vivo when FGF-2 was used as the stimulus. The peptide antagonist did not inhibit TNF-a binding to its receptor nor did it block the function of alphavbeta3, an integrin previously implicated in TNF-a and FGF- 2 mediated angiogenesis. These results demonstrate that angiogenic processes induced by TNF-alpha are mediated in part by agr;4 integrins possibly by a mechanism involving the induction of soluble VCAM-1.
肿瘤坏死因子-α（TNF-α）和成纤维细胞生长因子-2（FGF-2或bFGF）是血管生成的强效刺激因子。TNF-α可诱导内皮细胞表面血管细胞黏附分子-1（VCAM-1）的表达，而FGF-2则不能。最近已证实可溶性形式的VCAM-1可作为血管生成介质发挥作用。在此我们证明，针对VCAM-1或其α4整合素反受体的单克隆抗体在体外可抑制TNF-α诱导的内皮细胞迁移。针对大鼠α4整合素亚基的中和抗体可抑制TNF-α在大鼠角膜中诱导的体内血管生成。α4整合素的肽拮抗剂在体外可阻断TNF-α诱导的内皮细胞迁移，并在体内抑制大鼠角膜中的血管生成。当使用FGF-2作为刺激因子时，无论是在体外还是体内，均未观察到抗体或肽拮抗剂的抑制作用。该肽拮抗剂既不抑制TNF-α与其受体的结合，也不阻断αvβ3的功能，αvβ3是一种先前与TNF-α和FGF-2介导的血管生成有关的整合素。这些结果表明，TNF-α诱导的血管生成过程部分由α4整合素介导，可能是通过涉及可溶性VCAM-1诱导的机制实现的。
