Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61)

Connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61) are prototypical members of the CCN family which also contains nephroblastoma overexpressed (NOV) and Wnt-induced secreted proteins-1, -2 and -3 (WISP-1, -2, -3). These proteins function as extracellular matrix (ECM)-associated signaling molecules that contain structural modules allowing them to bind directly with other moieties in the pericellular environment. Although multiple target cell types have been identified for CCN proteins, there is strong evidence supporting a role for CTGF and CYR61 in the regulation of endothelial cell function and angiogenesis. Both CTGF and CYR61 can promote endothelial cell growth, migration, adhesion and survival in vitro and at least some of these effects are mediated through cell surface integrins. Both proteins are transcriptionally activated in endothelial cells in response to basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF), and endothelial cell proliferation and migration in vitro is reduced by antagonists of CTGF production or action. The expression pattern of CTGF and CYR61 in endothelial cells of vessels in situ supports a role for these molecules in normal endothelial homeostasis, as well as participating in the angiogenic process during embryonic development, placentation, tumor formation, fibrosis, and wound healing. CTGF or CYR61 knockout mice exhibit vascular defects during embryogenesis and fetal development. Both CTGF and CYR61 are intrinsically active in in vivo asssays for angiogenic activity. However, they can also regulate the production and/or activity of other angiogenic molecules (e.g. bFGF, VEGF) as well molecules that affect the integrity or stability of the ECM (e.g. collagen, matrix metalloproteases (MMPs), tissue inhibitors of MMPs (TIMPs)). Therefore, through their paracrine action as products of cells such as fibroblasts or smooth muscle cells or through their autocrine action as products of endothelial cells, CTGF and CYR61 participate in a variety of direct and indirect mechanisms by which angiogenesis is regulated at multiple control points.