Requisite role of p38 MAPK in mural cell recruitment during angiogenesis in the rat aorta model.
During the early stage of angiogenesis, neovascular sprouts are composed primarily of endothelial cells. As they mature, microvessels acquire a coating of mural cells, which are critical for the development and maintenance of a functional vasculature. Though growth factor regulation of mural cell recruitment has been extensively investigated, the intracellular signaling events involved in this process remain poorly understood. Among the intracellular kinases implicated in angiogenesis, the p38 MAPK has been shown to transduce signals critical for vascular remodeling and maturation. The rat aorta model of angiogenesis was used to further investigate the role of this signaling pathway in the recruitment of mural cells during angiogenesis. The p38 MAPK inhibitor SB203580 selectively blocked mural cell recruitment, resulting in the formation of naked endothelial tubes without mural cells. SB203580 inhibited angiopoietin-1-induced mural cell recruitment without influencing angiopoietin-1-stimulated endothelial sprouting. Adenoviral vector-mediated expression of a dominant negative form of p38 MAPK significantly reduced mural cell recruitment, whereas overexpression of a constitutively activated form of MKK6, an upstream activator of p38 MAPK, increased mural cell number. These results indicate that the p38 MAPK signaling pathway plays a critical role in mural cell recruitment during neovascularization and may represent a therapeutic target in angiogenesis-related disorders.
Zhu
Wen-Hui
WH
Department of Pathology, University of Washington, Seattle, WA, USA.
Han
Jiahuai
J
Nicosia
Roberto Francesco
RF
D000256:Adenoviridae / Q000235:genetics; D000803:Angiotensin I / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D007093:Imidazoles / Q000494:pharmacology; D048669:MAP Kinase Kinase 6; D008297:Male; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020286:Pericytes / Q000166:cytology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D000803:Angiotensin I; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C093642:SB 203580