MCP-1 mediates TGF-beta-induced angiogenesis by stimulating vascular smooth muscle cell migration.

Transforming growth factor-beta (TGF-beta) and its signaling mediators play crucial roles in vascular formation. Our previous microarray analysis identified monocyte chemoattractant protein-1 (MCP-1) as a TGF-beta target gene in endothelial cells (ECs). Here, we report that MCP-1 mediates the angiogenic effect of TGF-beta by recruiting vascular smooth muscle cells (VSMCs) and mesenchymal cells toward ECs. By using a chick chorioallantoic membrane assay, we show that TGF-beta promotes the formation of new blood vessels and this promotion is attenuated when MCP-1 activity is blocked by its neutralizing antibody. Wound healing and transwell assays established that MCP-1 functions as a chemoattractant to stimulate migration of VSMCs and mesenchymal 10T1/2 cells toward ECs. Furthermore, the conditioned media from TGF-beta-treated ECs stimulate VSMC migration, and inhibition of MCP-1 activity attenuates TGF-beta-induced VSMC migration toward ECs. Finally, we found that MCP-1 is a direct gene target of TGF-beta via Smad3/4. Taken together, our findings suggest that MCP-1 mediates TGF-beta-stimulated angiogenesis by enhancing migration of mural cells toward ECs and thus promoting the maturation of new blood vessels.