The Nexus between VEGF and NFκB Orchestrates a Hypoxia-Independent Neovasculogenesis

Nuclear Factor-Kappa B [NF kappa B] activation triggers the elevation of various pro-angiogenic factors that contribute to the development and progression of diabetic vasculopathies. It has been demonstrated that vascular endothelial growth factor [VEGF] activates NF kappa B signaling pathway. Under the ischemic microenvironments, hypoxia-inducible factor-1 [HIF-1] upregulates the expression of several proangiogenic mediators, which play crucial roles in ocular pathologies. Whereas YC-1, a soluble guanylyl cyclase [sGC] agonist, inhibits HIF-1 and NF kappa B signaling pathways in various cell and animal models. Throughout this investigation, we examined the molecular link between VEGF and NF kappa B under a hypoxia-independent microenvironment in human retinal microvascular endothelial cells [hRMVECs]. Our data indicate that VEGF promoted retinal neovasculogenesis via NF kappa B activation, enhancement of its DNA-binding activity, and upregulating NF kappa B/p65, SDF-1, CXCR4, FAK, alpha V beta 3, alpha 5 beta 1, EPO, ET-1, and MMP-9 expression. Conversely, YC-1 impaired the activation of NF kappa B and its downstream signaling pathways, via attenuating I kappa B kinase phosphorylation, degradation and activation, and thus suppressing p65 phosphorylation, nuclear translocation, and inhibiting NF kappa B-DNA binding activity. We report for the first time that the nexus between VEGF and NF kappa B is implicated in coordinating a scheme that upregulates several proangiogenic molecules, which promotes retinal neovasculogenesis. Our data may suggest the potential use of YC-1 to attenuate the deleterious effects that are associated with hypoxia/ischemia-independent retinal vasculopathies.