Angiogenesis is essential for tumor growth and metastasis. In the process of angiogenesis, the interaction between adhesive proteins of endothelial cells and extracellular matrix components plays an important role by mediating cell attachment, which is indispensable for their motility, and by transmitting the regulatory signals for cell locomotion and proliferation. In this study, we examined the hypothesis that CD44 expressed on the endothelial cell surface is involved in the angiogenesis process. The experiments using calf pulmonary artery endothelial cells (CPAE) and a human microvascular endothelial cell line (HMEC-I) show that a monoclonal antibody against CD44 (clone J 173) inhibits endothelial cell proliferation by about 30% and migration by 25-50%, and abolishes the stimulating effect of hyaluronan polysaccharides on endothelial cell migration and proliferation. This antibody also suppresses the capillary formation of CPAE in an in vitro model of angiogenesis using fibrin matrix. These results provide evidence of the involvement of endothelial-cell-associated CD44 in angiogenesis.o 1996 Wiley-Liss, Inc.Angiogenesis plays a fundamental role in many physiological and pathological processes including wound healing, tissue repair and tumor growth (Folkman, 1995). For the formation of a new vessel, migration of stimulated endothelial cells and subsequent tube formation virtually depend on the occurrence of timely and locally coordinated extracellular proteolysis, cell adhesion and activation during the cell migration. Therefore, the interaction of adhesive proteins expressed on the endothelial cell surface with the components of extracellular matrix is one of the factors determining the occurrence of angiogenesis. Perturbation of these interactions may abolish an ongoing angiogenesis process. For example, blocking the binding of the integrin molecule to matrix-associated vitronectin led to endothelial cell apoptosis and abolished tumor-induced angiogenesis in vivo (Brooks et al., 1994). Furthermore, the interaction of adhesive proteins with their endothelial cell-surface receptors may also activate the process of angiogenesis. For instance, endothelial cells could be stimulated by the surrounding fibrin I1 matrix to form capillary tubes in vitro (Chalupowicz et al., 1995). However, due to the complexity of the mechanisms involved in cell adhesion, the functions of many adhesive molecules on the endothelial cell surface still remain to be determined.One of the examples is CD44, discovered through its role in mediating leukocyte adhesion and lymphocyte homing (Haynes et al., 1989). Although several studies reported the presence of CD44 on endothelial cells such as human microvascular endothelial cells (HMEC-1) (Xu et al., 1994), bovine microvascular endothelial cells (BME) (Bourguignon et al., 1992) and human umbilical endothelial cells (HUVEC) (Liesveld et al., 1994), the role of CD44 expressed on the endothelial cell surface still remains to be clarified. CD44 is a transmembrane molecule with multiple isofo...

Abstract-Neovascularization of the atherosclerotic plaque is responsible for its weakening and consequently for the complications of vascular disease. Macrophages are a source of growth factors that can modulate angiogenesis. In this study, we analyzed the effect of oncostatin M (OSM) on angiogenesis, as it could be involved in the development of atherosclerosis. The effect of OSM was compared with those of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). On human dermal microvasculature endothelial cells (HMEC-1s), OSM (22.5 to 112.5 pmol/L) induced a dose-dependent increase in cell proliferation greater than that induced by the classic angiogenic factors vascular endothelial growth factor (VEGF; 543 pmol/L) and basic fibroblast growth factor (bFGF; 1.1 nmol/L). LIF (19 to 475 pmol/L) induced only a 30% increase in cell proliferation, and IL-6 had no effect. Furthermore, in a modified Boyden-chamber model, OSM, LIF, and IL-6 were chemoattractant for HMEC-1s. In a tridimensional gel of fibrin, OSM increased tube formation and tube length, which were already noticeable by day 3. LIF and IL-6 induced a weaker effect that was only obvious by day 10. The angiogenic effect of OSM was also demonstrated in vivo in a rabbit corneal model: OSM was more potent than LIF, the length of the neovessels being longer with OSM than with LIF, whereas IL-6 was without effect. We tested factors that could be involved in the proliferative effect of OSM on HMEC-1s. OSM induced only a slight increase in the urokinase receptor and a 60% increase in VEGF secretion, whereas it does not modify IL-8 secretion or bFGF levels. The effect of OSM seems to depend on endothelial cell origin and cell species: OSM (up to 112.5 pmol/L) did not induce human umbilical vein endothelial cell proliferation and even had a small inhibitory effect (17%) on calf pulmonary artery endothelial cells. In conclusion, OSM induces an angiogenic effect on capillary endothelial cells, which could be, at least in part, implicated in pathological processes such as atherosclerosis or tumor growth. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ oncostatin M Ⅲ leukemia inhibitory factor Ⅲ vascular endothelial growth factor I t is now established that the functional role of the macrophage extends far beyond its originally recognized role as a scavenger cell. Monocytes in particular are recognized as angiogenesis effector cells that produce a number of growth stimulators and inhibitors, proteolytic enzymes, and cytokines that can influence 1 or more steps in the angiogenesis cascade. It has been shown that activated monocytes or their culture supernatants induce new capillary growth in vitro and angiogenesis in vivo. 1,2 However, recent evidence also suggests that capillary regression may be mediated by monocytes by producing antiangiogenic factors in vitro and in vivo. [3][4][5] Thus, macrophages could be involved in both stimulation and suppression of angiogenesis.Because macrophages reside at the sites of atherosclerotic plaques in the vessel wall and because the...

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Hyaluronic acid (HA) is a glycosaminoglycan of the extracellular matrix. Its fragmentation by the hyaluronidase, secreted by tumor cells, facilitates tumor invasion and the HA degradation products generated stimulate angiogenesis. We report here that the HA-binding protein hyaluronectin (HN) inhibits the stimulatory effect of HA-derived fragments on the proliferation and migration of endothelial cells in vitro, and hampers the organization of endothelial cells into capillary-like structures. Since HN strongly inhibits endothelial cell adhesion to immobilized HA, it is postulated that HN acts by impairing the binding to endothelial cells of HA fragments generated by hyaluronidase, thereby neutralizing the effect of HA degradation products on angiogenesis. Our results reveal a new mechanism by which the angiogenesis induced by HA fragments is modulated by HN.

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Recently two metalloproteinase, disintegrin, cysteine proteins (MDCs), also called ADAMs were identified on endothelial cells. However the role of these ADAMs are not defined on these cells. In order to elucidate whether ADAMs associated with endothelial cells could be involved in angiogenesis, we have tested the effect of an inhibitor of ADAM (GL 129471) in models of angiogenesis in vitro. Our results showed that GL 129471 inhibited endothelial cell migration and adhesion and increased the number of cells in the G2/M phase leading to an inhibition of cell proliferation. The effects of GL 129471 are not mimicked by the endogenous matrix metalloproteinase inhibitor TIMP-2. These data suggest that ADAMs may play important role in angiogenesis and could provide a new target for inhibition of angiogenesis in cancers.