MCB Accepts, published online ahead of print on 14 July 2008

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Mol. Cell. Biol. doi:10.1128/MCB.00393-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Rap1a is a key regulator of FGF2-induced angiogenesis and together with Rap1b controls human endothelial cell functions

Jingliang Yan, Fang Li, David A. Ingram, and Lawrence A. Quilliam^*

Department of Biochemistry and Molecular Biology, Walther Cancer Institute, and Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis

^* To whom correspondence should be addressed. Email: lquillia{at}iupui.edu.

Angiogenesis, the formation of new blood vessels from existing vasculature, is primarily regulated by endothelial cell activity. We show herein that the Ras family GTPase Rap1 is a key regulator of angiogenesis by modulating endothelial cell functions. Blood vessel growth into FGF2-containing Matrigel plugs was absent from rap1a^-/- mice and aortic rings derived from rap1a^-/- mice failed to sprout primitive tubes in response to FGF2 when embedded in Matrigel. Knocking down either rap1a or rap1b, two closely related rap1 family members, in human micro-vascular endothelial cells (HMVECs) utilizing siRNA confirmed that Rap1 plays key roles in endothelial cell function. rap1a or 1b knockdown resulted in decreased adhesion to extracellular matrices and impaired cell migration. HMVEC monolayers lacking Rap1 had increased permeability and Rap1 deficient endothelial cells failed to form 3-D tubular structures when plated on Matrigel in vitro. Finally, the activation of ERK, p38, and Rac, important signaling molecules in angiogenesis, were all reduced in response to FGF2 when either Rap1 protein was depleted. These observations place Rap1 centrally in the human angiogenic process, suggest that both Rap1a and Rap1b proteins are required for angiogenesis and that Rap1 is a critical mediator of FGF-induced ERK activation.

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