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Molecular and Cellular Biology, April 1999, p. 2958-2966, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Fisp12/Mouse Connective Tissue Growth Factor Mediates Endothelial Cell Adhesion and Migration through Integrin alpha vbeta 3, Promotes Endothelial Cell Survival, and Induces Angiogenesis In Vivo

Alexander M. Babic, Chih-Chiun Chen, and Lester F. Lau*

Department of Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607-7170

Received 18 September 1998/Returned for modification 11 December 1998/Accepted 21 December 1998

Fisp12 was first identified as a secreted protein encoded by a growth factor-inducible immediate-early gene in mouse fibroblasts, whereas its human ortholog, CTGF (connective tissue growth factor), was identified as a mitogenic activity in conditioned media of human umbilical vein endothelial cells. Fisp12/CTGF is a member of a family of secreted proteins that includes CYR61, Nov, Elm-1, Cop-1/WISP-2, and WISP-3. Fisp12/CTGF has been shown to promote cell adhesion and mitogenesis in both fibroblasts and endothelial cells and to stimulate cell migration in fibroblasts. These findings, together with the localization of Fisp12/CTGF in angiogenic tissues, as well as in atherosclerotic plaques, suggest a possible role for Fisp12/CTGF in the regulation of vessel growth during development, wound healing, and vascular disease. In this study, we show that purified Fisp12 (mCTGF) protein promotes the adhesion of microvascular endothelial cells through the integrin receptor alpha vbeta 3. Furthermore, Fisp12 stimulates the migration of microvascular endothelial cells in culture, also through an integrin-alpha vbeta 3-dependent mechanism. In addition, the presence of Fisp12 promotes endothelial cell survival when cells are plated on laminin and deprived of growth factors, a condition that otherwise induces apoptosis. In vivo, Fisp12 induces 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 cells during blood vessel growth. Taken together with the recent finding that the related protein CYR61 also induces angiogenesis, we suggest that Fisp12/mCTGF and CYR61 comprise prototypes of a new family of angiogenic regulators that function, at least in part, through integrin-alpha vbeta 3-dependent pathways.


* Corresponding author. Mailing address: Department of Molecular Genetics, University of Illinois at Chicago College of Medicine, 900 South Ashland Ave., Chicago, IL 60607-7170. Phone: (312) 996-6978. Fax: (312) 996-7034. E-mail: lflau{at}uic.edu.


Molecular and Cellular Biology, April 1999, p. 2958-2966, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.



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