Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia

Abstract

CD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs) . IntroductionCD146 is a component of the endothelial junction primarily expressed in endothelial cells. It is involved in the control of cell and tissue architecture, as demonstrated by the regulation of its expression during endothelium monolayer formation, its involvement in the control of paracellular permeability, and its colocalization with the actin cytoskeleton. 1 Besides its structural role, CD146 is also involved in cell signaling. 2,3 We have recently demonstrated that CD146 is involved in the regulation of monocyte transendothelial migration. 4 Recent findings indicate that CD146 displays angiogenic properties. In one study, the authors showed that an anti-CD146 antibody, mAb AA98, displayed antiangiogenic properties in chicken chorioallantoic membrane assays and inhibited tumor growth in different xenografted human tumor models in mice. In a model of human umbilical vein endothelial cells (HUVECs), it was also shown that silencing CD146 with specific siRNA inhibited the proliferation and migration of the cells. [5][6][7] Of interest, we have established that CD146 also exists in a soluble form (sCD146) as the result of metalloprotease-dependent shedding of membrane CD146. 4,8 sCD146 is detectable in the human serum, and its level is modulated in different pathologies, such as inflammatory bowel diseases, 9 pathologic pregnancies, 10 and chronic renal failure. 11 However, its exact role is still largely unknown.Postischemic neovascularization occurs as a result of 2 mechanisms: angiogenesis, which relies on mature endothelial cells already present at the ischemic site; and vasculogenesis, which involves the homing and endothelial differentiation of endothelial progenitor cells (EPCs) mobilized from the bone marrow. 12,13 Different angiogenic factors have been shown to trigger angiogenesis and/or vasculogenesis by directly or indirectly stimulating proliferation, differentiation, and migration of mature or precursor cells. Among these factors, the more effective are fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), and angiopoietins (Ang). FGF-1 has been shown to stimulate the proliferation and differentiation of all cell types necessary for the constitution of an arterial vessel, including endothelial cells and smooth muscle cells. FGF-2 also promotes endothelial cell proliferation and organization of endothelial cells into capillary-like structures. 14 In vitro studies have clearly demonstrated that VEGF is a potent stimulator of angiogenesis, stimulating endothelial cell mitogenesis and migration, 15 and numerous clinical trials have been co...

Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through β1-integrin and VEGFR2

“…Unlike the experiments with HER1-HER4, we found that VEGFR2 was directly in the pathway of ScuPA-induced phosphorylation of ERK1/2 and Akt (Ser 473 ) (1,32,57). It is of note that siRNA to VEGFR2 has a greater effect on decreasing pAkt (Ser 473 ) than pERK1/2.…”

High-Throughput Screening of Surface Marker Expression on Undifferentiated and Differentiated Human Adipose-Derived Stromal Cells

“…28 Furthermore, soluble CD146 displays angiogenic properties and has been shown to promote neovascularization in ischemic models. 29 Given these findings and our data showing CD146 upregulation in adipogenically differentiated hASCs, CD146 enrichment of hASCs may represent a viable strategy before transplantation to facilitate angiogenesis in conjunction with adipogenesis in recipient sites with poor blood supply, such as in irradiated tissue or in individuals with a reduced capacity for neovascularization, such as elderly and diabetic patients.…”

CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis

“…41 Therefore, the synergistic effect between the combined Abs is because of the incomplete overlapping signaling of CD146 and VEGFR-2. In previous studies, we and others have found that CD146 can also function independently of VEGFR-2.…”