Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alpha(v)beta(3), promotes endothelial cell survival, and induces angiogenesis in vivo

Fisp12 was first identified as a secreted protein encoded by a growth facto r-inducible immediate-early gene in mouse fibroblasts, whereas its human or tholog. CTGF (connective tissue growth factor), was identified as a mitogen ic activity in conditioned media of human umbilical vein endothelial cells. Fisp12/CTGF is a member of a family of secreted proteins that includes CYR 61, Nov, Elm-1, Cop-1/WISP-2, and WISP-3. Fisp12/CTGF has been shown to pro mote cell adhesion and mitogenesis in both fibroblasts and endothelial cell s and to stimulate cell migration in fibroblasts, These findings, together with the localization of Fisp12/CTGF in angiogenic tissues, as well as in a therosclerotic plaques, suggest a possible role for Fisp12/CTGF in the regu lation of vessel growth during development, wound healing, and vascular dis ease. In this study, we show that purified Fisp12 (mCTGF) protein promotes the adhesion of microvascular endothelial cells through the integrin recept or alpha(v)beta(3). Furthermore. Fisp12 stimulates the migration of microva scular endothelial cells in culture, also through an integrin-alpha(v)beta( 3)-dependent mechanism. In addition, the presence of Fisp12 promotes endoth elial cell survival when cells are plated on laminin and deprived of growth factors, a condition that otherwise Induces apoptosis. In vivo, Fisp12 ind uces neovascularization in rat corneal micropocket implants. These results demonstrate that Fisp12 is a novel angiogenic inducer and suggest a direct role for Fisp12 in the adhesion, migration, and survival of endothelial cel ls during blood vessel growth. Taken together with the recent finding th;lt the related protein CYR61 also induces angiogenesis, we suggest that Fisp1 2/mCTGF and CYR61 comprise prototypes of a new family of angiogenic regulat ors that function, at least in part, through integrin-alpha(v)beta(3)-depen dent pathways.