MCP-1 muscles in on pericytes

In this issue of Blood, Ma and colleagues demonstrate that TGF-β supports angiogenesis through up-regulation of the MCP-1 chemokine, which stimulates the recruitment of vascular smooth muscle cells or pericytes toward endothelial cells.

Angiogenesis, or new blood vessel formation, involves proliferation and migration of endothelial cells induced by vascular endothelial growth factor (VEGF), degradation of subendothelial matrices and basement membrane with metalloproteinases (MMPs), branching, stabilization of newly formed endothelial cords by angiopoietin-1, and disassembly, reassembly, and expansion of endothelial cords by angiopoietin 2. Angiopoietin-1 maintains vascular stability by recruitment of vascular growth smooth muscle cells or pericytes.

Of the numerous proangiogenic growth factors that have been described, some are relatively specific for endothelial cells, such as VEGF and its KDR receptor as well as angiopoietins 1 and 2 and their Tie-2 receptors. Others, such as transforming growth factor-β (TGF-β), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and the chemokines interleukin-8 (IL-8), growth-related oncogene-α (GRO-α), and monocyte chemoattractant protein-1 (MCP-1) are less specific for endothelial cells. Their mode of action on endothelial cells is poorly characterized.

Chemokines (chemotactic cytokines) are small heparin-binding cysteine-containing proteins that direct movement of granulocytes, lymphocytes, and dendritic cells to sites of inflammation. They induce various physiologic functions when binding to their receptors, which are present on various tissues, including endothelial cells and smooth muscle cells. They segregate into 4 families.^1,2  The largest family of chemokines is designated CC (first 2 of 4 cysteines adjacent to each other). A subset of a second family of CXC chemokines (first 2 cysteines separated by a nonconserved amino acid) containing the NH-2 terminus ELR amino acid motif have been shown to stimulate angiogenesis by binding to a common receptor, CXCR2, on endothelial cells.

It is of interest that thrombin-induced angiogenesis is also stimulated via the up-regulation of a CXC chemokine, GRO-α, which binds to a CXCR2 receptor, resulting in the up-regulation of VEGF, KDR, angiopoietin-2, MMP-1, MMP-2, and CD31.³  It is also of interest that TGF-β up-regulates VEGF and PDGF^4,5  as well as MCP-1.

In this issue of Blood, Ma and colleagues demonstrate that the mechanism of action of TGF-β on stimulating angiogenesis is through up-regulation of the CC chemokine MCP-1. In a series of elegant experiments they demonstrate that TGF-β activates the promoter region of MCP-1 by initiating binding of the transcription factors Smad3 and Smad4 to the MCP-1 promoter. This leads to the recruitment of pericytes for angiogenic stability. Others have shown that MCP-1–induced angiogenesis is also mediated by VEGF.⁶  Thus, a CC chemokine is also capable of stimulating angiogenesis following its up-regulation by VEGF as well as TGF-β and perhaps other vascular growth factors yet to be determined.

These observations tie inflammation to angiogenesis. What is a possible pathophysiologic relevance for these observations? Tumor cells secrete MCP-1. The requirement of tumor-induced angiogenesis for tumor growth is well established. The ability of tumor cells to secrete VEGF, bFGF, and PDGF is well recognized. The addition of the chemokines GRO-α and MCP-1 contributes to this panoply of tumor-secreting angiogenesis growth factors.