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J. Biol. Chem., Vol. 283, Issue 7, 3942-3950, February 15, 2008

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KLF2 Transcription Factor Modulates Blood Vessel Maturation through Smooth Muscle Cell Migration^*

From the Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267

Vasculogenesis, angiogenesis, and maturation are three major phases of the development of blood vessels. Although many receptors required for blood vessel formation have been defined, the intracellular signal transduction pathways involved in vascular maturation remain unclear. KLF2^–/– embryos fail to develop beyond 13.5 days because of a lack of blood vessel stabilization. The molecular mechanism of KLF2 function in embryonic vascular vessels is still largely unknown. Here we show a normal development pattern of endothelial cells in KLF2^–/– embryos but a defect of smooth muscle cells at the dorsal side of the aorta. This phenotype results from arrested vascular maturation characterized by the failure of mural cells to migrate around endothelial cells. This migration defect is also observed when platelet-derived growth factor-B (PDGF) controlled migration is studied in murine embryonic fibroblast (MEF) cells from KLF2^–/– animals. In addition, KLF2^–/– MEFs exhibit a significant growth defect, indicating that KLF2 is required to maintain the viability of MEF cells. The PDGF signal is mediated through the Src signaling pathway, and a downstream target of KLF2 is sphingosine 1-phosphate receptor 1. These studies demonstrate that KLF2 is required for smooth muscle cell migration and elucidate a novel mechanism involving communication between PDGF and KLF2 in vascular maturation.

Received for publication, September 20, 2007 , and in revised form, December 5, 2007.

^* This work was supported by National Institutes of Health Grant RO1 HL 57281. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267. E-mail: jerry.lingrel{at}uc.edu.

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