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Molecular and Cellular Biology, September 2008, p. 5803-5810, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00393-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Rap1a Is a Key Regulator of Fibroblast Growth Factor 2-Induced Angiogenesis and Together with Rap1b Controls Human Endothelial Cell Functions{triangledown}

Jingliang Yan,1,2 Fang Li,3 David A. Ingram,1,3 and Lawrence A. Quilliam1,2*

Department of Biochemistry and Molecular Biology,1 Walther Cancer Institute,2 Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana3

Received 7 March 2008/ Returned for modification 11 April 2008/ Accepted 2 July 2008

Angiogenesis, the formation of new blood vessels from existing vasculature, is regulated primarily by endothelial cell activity. We show herein that the Ras family GTPase Rap1 has a key role in the regulation of angiogenesis by modulating endothelial cell functions. Blood vessel growth into fibroblast growth factor 2 (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 the tissue was embedded in Matrigel. Knocking down either rap1a or rap1b, two closely related rap1 family members, in human microvascular endothelial cells (HMVECs) by utilizing siRNA confirmed that Rap1 plays key roles in endothelial cell function. The rap1a or rap1b 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 three-dimensional tubular structures when they were plated on Matrigel in vitro. Finally, the activation levels of extracellular signal-regulated kinase (ERK), p38, and Rac, which are important signaling molecules in angiogenesis, were all reduced in response to FGF2 when either of the Rap1 proteins was depleted. These observations place Rap1 centrally in the human angiogenic process and suggest that both the Rap1a and Rap1b proteins are required for angiogenesis and that Rap1 is a critical mediator of FGF-induced ERK activation.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., Room 4053, Indianapolis, IN 46202. Phone: (317) 274-8550. Fax: (317) 274-4686. E-mail: lquillia{at}iupui.edu

{triangledown} Published ahead of print on 14 July 2008.

Molecular and Cellular Biology, September 2008, p. 5803-5810, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00393-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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