Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice. Blood 2008 Mar 01;111(5):2647-56
Date
11/13/2007Pubmed ID
17993608Pubmed Central ID
PMC2254536DOI
10.1182/blood-2007-08-109710Scopus ID
2-s2.0-41949111990 (requires institutional sign-in at Scopus site) 146 CitationsAbstract
Angiogenesis is the main mechanism of vascular remodeling during late development and, after birth, in wound healing. Perturbations of angiogenesis occur in cancer, diabetes, ischemia, and inflammation. While much progress has been made in identifying factors that control angiogenesis, the understanding of the precise molecular mechanisms involved is incomplete. Here we identify a small GTPase, Rap1b, as a positive regulator of angiogenesis. Rap1b-deficient mice had a decreased level of Matrigel plug and neonatal retinal neovascularization, and aortas isolated from Rap1b-deficient animals had a reduced microvessel sprouting response to 2 major physiological regulators of angiogenesis: vascular endothelial growth factor (VEGF) and basic fibroblasts growth factor (bFGF), indicating an intrinsic defect in endothelial cells. Proliferation of retinal endothelial cells in situ and in vitro migration of lung endothelial cells isolated from Rap1b-deficient mice were inhibited. At the molecular level, activation of 2 MAP kinases, p38 MAPK and p42/44 ERK, important regulators of endothelial migration and proliferation, was decreased in Rap1b-deficient endothelial cells in response to VEGF stimulation. These studies provide evidence that Rap1b is required for normal angiogenesis and reveal a novel role of Rap1 in regulation of proangiogenic signaling in endothelial cells.
Author List
Chrzanowska-Wodnicka M, Kraus AE, Gale D, White GC 2nd, Vansluys JAuthors
Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinGilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Aorta
Bromodeoxyuridine
Cell Movement
Cell Proliferation
Collagen
Drug Combinations
Endothelial Cells
Humans
In Vitro Techniques
Laminin
Lung
MAP Kinase Signaling System
Mice
Neovascularization, Pathologic
Proteoglycans
Retina
Retinal Neovascularization
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
Wound Healing
rap GTP-Binding Proteins