Fig. 7.

Distinct roles of VEGF vs. R-Ras-mediated Akt signaling in angiogenesis. VEGF and R-Ras signaling activate Akt in different manners. Akt accumulates in perinuclear region upon activation by VEGF. In contrast, R-Ras-dependent Akt activation results in the accumulation of activated Akt along the microtubule cytoskeleton as well as at the perinuclear region. The effect of the VEGF-Akt signaling is largely skewed toward vessel sprouting and permeability induction, and it is insufficient for driving vessel lumenization by itself (green). The R-Ras-Akt signaling, on the other hand, promotes lumenogenesis and supports the lumen structure with the stable cytoskeletal architecture of microtubules (blue). R-Ras also limits excessive, nonproductive endothelial sprouting, and block the VEGF-induced disruption of adherens junction (AJ) to maintain endothelial barrier integrity (Sawada et al.¹¹). Thus, the VEGF and R-Ras pathways are complementary to each other to generate functional blood vessels for tissue recovery from ischemia