R-Ras Inhibits VEGF-Induced p38MAPK Activation and HSP27 Phosphorylation in Endothelial Cells

Area of Science:

• Molecular Biology
• Cell Biology
• Angiogenesis Research

Background:

• R-Ras, a small GTPase, is crucial for mature blood vessel function and inhibits pathological angiogenesis.
• R-Ras influences signaling in endothelial cells, pericytes, and smooth muscle cells, impacting vessel remodeling.
• R-Ras suppresses VEGF-induced permeability and sprouting, promoting vessel normalization in mice.

Purpose of the Study:

• To investigate the molecular mechanisms by which R-Ras regulates endothelial cell signaling and angiogenic activities.
• To determine the role of R-Ras in the VEGF-dependent activation of stress-activated protein kinase-2/p38 mitogen-activated protein kinase (SAPK2/p38MAPK) and heat-shock protein 27 (HSP27) in endothelial cells.

Main Methods:

• Investigated the effect of R-Ras on VEGF-induced activation of p38MAPK and phosphorylation of HSP27 in endothelial cells.
• Analyzed changes in actin cytoskeleton, membrane protrusion, and endothelial cell migration.
• Utilized RNA interference to silence endogenous R-Ras and employed a p38MAPK inhibitor (SB203580) to assess pathway involvement.

Main Results:

• R-Ras significantly suppressed VEGF-dependent activation of p38MAPK and HSP27 phosphorylation in endothelial cells.
• R-Ras inhibition of p38MAPK and HSP27 correlated with altered actin cytoskeleton, reduced membrane protrusion, and inhibited cell migration.
• Silencing R-Ras enhanced VEGF-stimulated cell migration and protrusion, effects reversed by p38MAPK inhibition.

Conclusions:

• R-Ras plays a critical role in regulating endothelial cell angiogenic activities.
• R-Ras exerts its function, in part, by inhibiting the p38MAPK-HSP27 signaling axis downstream of VEGF.
• These findings elucidate a novel mechanism for R-Ras in controlling blood vessel formation and stabilization.