p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2–stimulated angiogenesis

Abstract

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.

Antagonistic control of cell fates by JNK and p38-MAPK signaling

“…Mouse embryonic fibroblasts (MEFs) isolated from mkk7 mutant embryos display impaired JNK and Jun activation, reduced cell proliferation, premature senescence, as well as augmented susceptibility to stressinduced aging ( Figure 1 and Wada et al 6 ). In contrast, activation of p38-MAPK can also result in premature senescence of MEFs, 7 whereas pharmacological p38-MAPK inhibition induces increased cell proliferation, 8 To assess functional hierarchies and potential molecular crosstalks between the JNK and p38-MAPK stress pathways in cell fate decisions, we tested the effects of p38-MAPK modulation in mkk7 À/À MEFs. Surprisingly, inhibition of p38-MAPKa/b using the selective inhibitor SB202190 restored the proliferation of mkk7-deficient MEFs to that of MKK7-expressing control cells (Figure 1a).…”

MKK signaling and vascularization

“…In this system, fibroblast growth factor-induced angiogenesis causes sustained ERK activity in endothelial cells and can be blocked by inhibition of Raf-1 (Hood et al, 2003) or MEK1 and MEK2 activity (Eliceiri et al, 1998). Interestingly, although fibroblast growth factor also causes sustained activation of p38 MAPK, p38 MAPK inhibition with SB202190 does not inhibit neovascularization but rather enhances it (Matsumoto et al, 2002), indicating that balanced p38 MAPK activity may be essential for neovascularization of chick chorioallantoic membrane.…”

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

“…Under these conditions, endothelial cells invade the substratum and organize capillary-like structures with a hollow lumen [36]. FGF2 enhances this response in type I collagen gel [37] possibly via a p38-dependent signaling pathway [38]. Endothelial cell morphogenesis can be induced by FGF2 also using three-dimensional fibrin gels [39].…”