Role of Integrin αvβ3 in Vascular Biology

Abstract

IntroductionA defining characteristic of vascular cells is their adhesive status. The predominant cells of the blood vessel, endothelial cells (EC) and smooth muscle cells (SMC), are normally adherent but can be induced to migrate in response to vascular injury and angiogenic stimuli. The circulating blood cells are ordinarily nonadhesive but can rapidly acquire an adhesive phenotype in response to physiologic and pathophysiologic stimuli. As prime examples, platelets become adherent to the subendothelial matrix and to one another during thrombus formation, and leukocytes first adhere to EC and then transmigrate during the inflammatory response. At a molecular level, the adhesive properties of the vascular cells are determined by the adhesion receptors on their cell-surface and the functional state of these receptors. To match the variety of requisite cellular adhesive reactions, the repertoire of adhesion receptors expressed by vascular cells is broad. Multiple representatives of the immunoglobulin-like, the selectin, the cadherin and the integrin families of adhesion receptors are present on and have been implicated in the functions of the vascular cells. The importance of these adhesion receptors in vascular cell function is underscored by the severe pathogenetic consequences of their congenital deficiencies, such as in Glanzmann’s thrombasthenia, LAD (Leucocyte Adhesion deficiency) I and LAD II (1-3).The integrins are the largest and most broadly distributed of the families of cellular adhesion receptors. Of the integrins, αvβ3, originally identified as the vitronectin receptor, is particularly widely distributed. It is expressed at variable density on many types of vascular cells. Obviously, the adhesive properties of a cell are determined by its full repertoire of adhesion receptors. As an example, the adhesion of EC to fibrinogen/fibrin is mediated by no fewer than five receptors. Nevertheless, it is possible to dissect out the contributions of individual adhesion receptors, and αvβ3 has been implicated in many functional responses of vascular cells. This review focusses upon the role of αvβ3 in vascular cell biology. Other contributions of this multifunctional receptor, such as its role in neoplastic growth and invasion and in osteoclast-mediated bone resorption, are beyond the scope of this article and have been reviewed elsewhere (4, 5).

Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

“…Integrins constitute a large family of cell membrane receptors for extracellular matrix proteins and regulate cell adhesion and migration (Clyman et al, 1992;Preissner and Sei ert, 1998;Byzova et al, 1998;Slepian et al, 1998). VN is a substrate (ligand) for four integrin receptors, a v b 1 , a v b 3 , a v b 5 and a IIb b 3 .…”

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

“…5 Ligand binding to these receptors through specific RGD motifs leads to complex intracellular signaling resulting in endothelial cell survival. 3,6,7 Consequently, blocking of these receptors with specific antibodies or RGD peptides results in endothelial cell apoptosis in vitro and suppression of angiogenesis in vivo, with subsequent suppression of tumor growth. 2,4 We have recently shown that the cyclic RGD pentapeptide EMD 121974, a specific ␣v-integrin antagonist, inhibited growth of brain tumor cell lines xenotransplanted into the forebrain of nu/nu mice, resulting in long-term survival.…”

Anti-Inflammatory Effects of αv Integrin Antagonism in Acute Kidney Allograft Rejection

“…Ligands for ␣ v integrins, which include osteopontin, fibronectin, fibrinogen, and MMP-2, are also known to be expressed and increased in allograft rejection, partly by tubular epithelia and partly by interstitial cells. 8,18,19 All these data led us to presume that ␣ v integrins might have potent inflammatory actions in acute renal allograft rejection, and abrogation of their functions might reduce rejection phenomena.…”

“…The cells that express high levels of ␣ v ␤ 3 include activated macrophages and endothelial cells. 4,8,9 Endothelial cells are primary targets in allograft rejection; macrophages represent a major mononuclear cell population in rejection. 10 Integrin ␣ v ␤ 3 has also been found in neutrophils, vascular smooth muscle cells, mesangial cells, tubular epithelial cells, and fibroblasts.…”

“…10 Integrin ␣ v ␤ 3 has also been found in neutrophils, vascular smooth muscle cells, mesangial cells, tubular epithelial cells, and fibroblasts. 8,11 Its expression is modulated by several cytokines [eg, interleukin (IL)-4, tumor necrosis factor-␣] and growth factors (eg, platelet-derived growth factor, fibroblast growth factor). ␣ v ␤ 3 itself can interact and modulate the expression of growth factors/growth factor receptors (eg, platelet-derived growth factor, vascular endothelial growth factor receptor-1) and release of cytokines (eg, tumor necrosis factor-␣, interferon-␥) in different cell types, [12][13][14] and elevated levels of these mediators have been detected in transplanted organs.…”