p38 MAP Kinase—a molecular switch between VEGF‐induced angiogenesis and vascular hyperpermeability

Abstract

Vascular endothelial growth factor (VEGF) is not only essential for vasculogenesis and angiogenesis but also is a potent inducer of vascular permeability. Although a dissection of the molecular pathways between angiogenesis- and vascular permeability-inducing properties would be desirable for the development of angiogenic and anti-angiogenic therapies, such mechanisms have not been identified yet. Here we provide evidence for a role of the p38 MAPK as the signaling molecule that separates these two processes. Inhibition of p38 MAPK activity enhances VEGF-induced angiogenesis in vitro and in vivo, a finding that was accompanied by prolonged Erk1/2 MAPK activation, increased endothelial survival, and plasminogen activation. Conversely, the same inhibitors abrogate VEGF-induced vascular permeability in vitro and in vivo. These dualistic properties of p38 MAPK are relevant not only for therapeutic angiogenesis but also for reducing edema formation and enhancing tissue repair in ischemic diseases.

p38 MAPK as a negative regulator of VEGF/VEGFR2 signaling pathway in serum deprived human SK-N-SH neuroblastoma cells

“…This observation is also consistent with the mechanism of action of SB202190, which inhibits p38 MAPK activity but not kinase phosphorylation [26]. Accordingly, these results implicate p38 MAPK as a negative regulator of VEGF-mediated neuroprotection and are consistent with previous reports with endothelial cells that activated p38 MAPK exerts opposing effects on FGF-2 or VEGF-mediated survival [9,16].…”

“…The fact that SB202190 promoted survival without reducing p38 MAPK phosphorylation (Fig. 1D) was previously observed in degenerating motor neurons [4] and in endothelial cells [9]. This observation is also consistent with the mechanism of action of SB202190, which inhibits p38 MAPK activity but not kinase phosphorylation [26].…”

“…In endothelial cells, VEGF signaling through VEGFR2 promoted survival by preventing caspase-3 cleavage and p38 MAPK phosphorylation [25] while p38 MAPK inhibition enhanced ERK1/2 activation by VEGF [9]. In stressed neuronal cells, VEGF signals survival through its cognate receptor VEGFR2 and the downstream activation of the PI3K/Akt and MEK/ERK1/2 pathways [16,27] and by suppressing the activation of caspase-3 [10,16] and p38 MAPK [13].…”

“…In stressed neuronal cells, VEGF signals survival through its cognate receptor VEGFR2 and the downstream activation of the PI3K/Akt and MEK/ERK1/2 pathways [16,27] and by suppressing the activation of caspase-3 [10,16] and p38 MAPK [13]. However, the exact role of p38 MAPK in VEGF-mediated signaling under stressful conditions is unclear since VEGF was shown to stimulate p38 MAPK after brain hypoxia [9] and inhibit its activation after retinal ganglion cell axotomy [13]. Using human SK-N-SH neuroblastoma cells as a neuronal model, we showed previously that serum deprivation induces an upregulation in the expression of VEGF and VEGFR2 which function concomitantly to signal survival through the activation of the PI3K/Akt and MEK/ERK1/2 pathways [7].To extend these studies, we investigated whether p38 MAPK influenced the signaling of VEGF-mediated pathways that counteract caspase activation in serum deprived SK-N-SH cells.…”

Vascular endothelial growth factor in eye disease

“…However, phosphorylation of Tyr1212/1214 has been implicated in VEGF-induced actin remodeling through the sequential activation of CDC42 and p38 MAPK (Lamalice et al, 2004). Inhibition of p38 MAPK augments VEGFinduced angiogenesis in the chicken chorioallantoic membrane (CAM) assay (Issbrucker et al, 2003;, without an accompanying increase in vascular permeability (Issbrucker et al, 2003). Moreover, p38 MAPK induces phosphorylation of heat-shock protein-27 (HSP27), a molecular chaperone that positively regulates VEGFinduced actin reorganization and migration (McMullen et al, 2005;Rousseau et al, 1997).…”