The angiogenic factor CCN1 promotes adhesion and migration of circulating CD34+ progenitor cells:: potential role in angiogenesis and endothelial regeneration

Tissue regeneration involves the formation of new blood vessels regulated by angiogenic factors. We reported recently that the expression of the angiogenic factor CCN1 is up-regulated under various pathophysiologic conditions within the cardiovascular system. Because CD34(+) progenitor cells participate in carcliovascular tissue regeneration, we investigated whether CCN1-detected for the first time in human plasma-promotes the recruitment of CD34(+) progenitor cells to endothelial cells, thereby enhancing endothelial proliferation and neovascularization. In this study, we demonstrated that CCN1 and supernatants from CCN1-stimulated human CD34(+) progenitor cells promoted proliferation of endothelial cells and angiogenesis in vitro and in vivo. In addition, CCN1 induced migration and trans-endothelial migration of CD34(+) cells and the release of multiple growth factors, chemokines, and matrix metalloproteinase-9 (MMP-9) from these cells. Moreover, the CCN1-specific integrins UM132 and OLVP3 are expressed on CD34(+) cells and CCN1 stimulated integrin-dependent signaling. Furthermore, integrin antagonists (RGDpeptides) suppressed both binding of CCN1 to CD34(+) cells and CCN1-induced adhesion of CD34(+) cells to enclothelial cells. These data suggest that CCN1 promotes integrin-dependent recruitment of CD34(+) progenitor cells to enclothelial cells, which may contribute to paracrine effects on angiogenesis and tissue regeneration.