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 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.
Chrzanowska-Wodnicka
Magdalena
M
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201, USA. magdalena.wodnicka@bcw.edu
Kraus
Anna E
AE
Gale
Daniel
D
White
Gilbert C
GC
Vansluys
Jillian
J
D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000378:metabolism; D001973:Bromodeoxyuridine; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007797:Laminin; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011509:Proteoglycans; D012160:Retina / Q000473:pathology; D015861:Retinal Neovascularization; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing; D020668:rap GTP-Binding Proteins / Q000172:deficiency* / Q000378:metabolism
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins; D001973:Bromodeoxyuridine