Find VEGFA Products Interaction Network for VEGFA VEGFA Details

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Synonyms: Gd-vegf, MGC70609, VEGF, Vegf-3, VEGF-E, VEGF1, VEGF120, Vegf164, Vegf165, Vegf188, VEGFA, Vegfa 188, VPF, VPF/VEGF

VEGF and S-1P Signaling

Angiogenesis requires the detachment and movement of endothelial cells through basement membranes to new locations (chemotaxis), followed by proliferation and tube and vascular barrier formation. Vascular endothelial growth factor (VEGF) and sphingosine-1-phosphate (SPP/S-1P/S1P) are important mediators of angiogenesis. The predominant endothelial cell receptor for VEGF and is VEGFR-2 (Flk1/KDR) and for S-1P the EDG receptors EDG-1/S1P1 and EDG-3/S1P3.

VEGF activation of VEGFR-2 leads to the stimulation of the phosphoinositol-3 kinase (PI3-K) pathway and subsequent activation of the downstream kinase, Akt/PKB. Akt/PKB mediates cell survival signaling by phosphorylating several factors involved in apoptosis machinery including: caspase-9, BCL2-antagonist of cell death (BAD), forkhead in rhabdomyosarcoma-like 1 (FKHRL1); IκB kinase, IKKalpha (an NFkappaBp65 activator). Akt/PKB stimulates protein synthesis by turning off constitutively active glycogen synthase kinase-3 (GSK3) and turning on mTOR (TORC1). Akt/PKB promotes cell-cycle progression by phosphorylating cyclin-dependent kinase (CDK) inhibitors p27(Kip1) and p21(CIP1). Akt/PKB attenuates the action of the second messenger cAMP by activating the cAMP phosphodiesterases-3B (PDE-3B). In endothelial cells, Akt also phosphorylates and activates endothelial nitric oxide synthase (eNOS) which increases nitric oxide (NO) levels. The activation of VEGFR-2 also activates a CrkII-dependent pathway that induces membrane ruffling and cell movement.

Sphingosine-1-phosphate (S-1P) produced by endothelial cells or blood platelets is a potent endothelial cell chemo-attractant and mediator of cell survival and growth. The predominant endothelial receptor EDG-1 is linked to a G(i)-trimeric GTPase. The activation of EDG-1 by S-1P is linked to the promotion of angiogenesis via the elevation of calcium/calmodulin activity and transactivation of the VEGFR-2 receptor. Transactivation of VEGFR-2 via EDG-1 activation involves its phosphorylation by an EDG-1 activated Src kinase. The concerted effects of calmodulin activation and AKT phosphorylation synergistically elevate eNOS activity and promote cell survival, protein synthesis and motility.