Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice

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 understan...

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Bibliographic Details
Published in:Blood 2008-03, Vol.111 (5), p.2647-2656
Main Authors: Chrzanowska-Wodnicka, Magdalena, Kraus, Anna E., Gale, Daniel, White, Gilbert C., VanSluys, Jillian
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Aorta - metabolism
Bromodeoxyuridine
Cell Movement
Cell Proliferation
Collagen
Drug Combinations
Endothelial Cells - enzymology
Endothelial Cells - pathology
Hemostasis, Thrombosis, and Vascular Biology
Humans
In Vitro Techniques
Laminin
Lung - cytology
MAP Kinase Signaling System
Mice
Neovascularization, Pathologic - pathology
Proteoglycans
rap GTP-Binding Proteins - deficiency
rap GTP-Binding Proteins - metabolism
Retina - pathology
Retinal Neovascularization
Vascular Endothelial Growth Factor A - blood
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Wound Healing
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-08-109710