p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis.
The p38 mitogen-activated protein kinase (p38) is activated in response to environmental stress and inflammatory cytokines. Although several growth factors, including fibroblast growth factor (FGF)-2, mediate activation of p38, the consequences for growth factor-dependent cellular functions have not been well defined. We investigated the role of p38 activation in FGF-2-induced angiogenesis. In collagen gel cultures, bovine capillary endothelial cells formed tubular growth-arrested structures in response to FGF-2. In these collagen gel cultures, p38 activation was induced more potently by FGF-2 treatment compared with that in proliferating cultures. Treatment with the p38 inhibitor SB202190 enhanced FGF-2-induced tubular morphogenesis by decreasing apoptosis, increasing DNA synthesis and cell proliferation, and enhancing the kinetics of cell differentiation including increased expression of the Notch ligand Jagged1. Overexpression of dominant negative mutants of the p38-activating kinases MKK3 and MKK6 also supported FGF-2-induced tubular morphogenesis. Sustained activation of p38 by FGF-2 was identified in vascular endothelial cells in vivo in the chick chorioallantoic membrane (CAM). SB202190 treatment enhanced FGF-2-induced neovascularization in the CAM, but the vessels displayed abnormal features indicative of hyperplasia of endothelial cells. These results implicate p38 in organization of new vessels and suggest that p38 is an essential regulator of FGF-2-driven angiogenesis.
Matsumoto
Taro
T
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, S-751 85, Sweden.
Turesson
Ingela
I
Book
Majlis
M
Gerwins
Pär
P
Claesson-Welsh
Lena
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D004247:DNA / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines / Q000494:pharmacology; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009024:Morphogenesis / Q000187:drug effects; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D048051:p38 Mitogen-Activated Protein Kinases
D002135:Calcium-Binding Proteins; D016228:Endothelial Growth Factors; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008565:Membrane Proteins; D011506:Proteins; D011725:Pyridines; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole