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.
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