CCN3-induced activities in cutaneous wound healing, angiogenesis, and proliferative restenosis

CCN3 (Nov) is a matricellular protein and a member of the CCN family. CCN3 is expressed during development, and altered expression has been observed in a variety of tumors. To understand its biological functions, the activities of purified recombinant CCN3 were investigated.; CCN3 is highly expressed in granulation tissue of cutaneous wounds 5--7 days after injury. Purified CCN3 supports fibroblast adhesion through integrins alpha 5beta1 and alpha6beta1, and induces fibroblast chemotaxis through integrin alphavbeta5. CCN3 is a novel ligand of integrins alphavbeta5 and alpha5beta1 as shown in a solid phase binding assay. CCN3 also enhances basic fibroblast growth factor-induced DNA synthesis. Furthermore, CCN3 upregulates expression of specific genes, and interacts with TGF-beta1 in an antagonistic or synergistic manner to regulate the expression of these genes. Also, CCN3 expression is regulated by serum and growth factors. These findings support a role for CCN3 in cutaneous wound healing in skin fibroblasts.; In endothelial cells, CCN3 supports cell adhesion, induces chemotaxis, and promotes cell survival. Mechanistically, CCN3 supports endothelial cell adhesion through integrins alphavbeta3, alpha 5beta1, alpha6beta1, and HSPGs, and-induces migration through integrins alphavbeta3 and alpha5beta1, CCN3 is a novel ligand of integrin alpha vbeta3 as shown in a solid phase binding assay. Furthermore, CCN3 induces neovascularization when implanted in rat corneas. Together, these findings show that CCN3 acts directly upon endothelial cells to stimulate pro-angiogenic activities and induces angiogenesis in vivo.; Ellis et al. (Arterioscler Thromb Vasc Biol, 2000; 20: 1912--9) showed that CCN3 is strongly expressed in the muscular media in uninjured vessels and in the neo-intima during proliferative restenosis. In smooth muscle cells, CCN3 supports adhesion through integrin alpha 6beta1 and HSPGs and promotes migration through integrin alpha 6beta1 and HSPGs. Also, CCN3 is capable of inducing expression of MMP1 and MMP2 in VSMCs. Furthermore, CCN3 expression is regulated by growth factors important in proliferative restenosis. Together, these results suggest that CCN3 can act on VSMCs to support neo-intimal formation and regulate vessel stenosis.