Abstract

Nuclear Factor-Kappa B [NFκB] 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 NFκB 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 NFκB signaling pathways in various cell and animal models. Throughout this investigation, we examined the molecular link between VEGF and NFκB under a hypoxia-independent microenvironment in human retinal microvascular endothelial cells [hRMVECs]. Our data indicate that VEGF promoted retinal neovasculogenesis via NFκB activation, enhancement of its DNA-binding activity, and upregulating NFκB/p65, SDF-1, CXCR4, FAK, αVβ3, α5β1, EPO, ET-1, and MMP-9 expression. Conversely, YC-1 impaired the activation of NFκB and its downstream signaling pathways, via attenuating IκB kinase phosphorylation, degradation and activation, and thus suppressing p65 phosphorylation, nuclear translocation, and inhibiting NFκB-DNA binding activity. We report for the first time that the nexus between VEGF and NFκB is implicated in coordinating a scheme that upregulates several pro-angiogenic 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.

Highlights

  • Angiogenesis is the formation of new blood vessels and capillary beds from existing vessels, which plays a fundamental role in physiological and pathological processes

  • To determine whether YC-1 [Fig. 1A] could suppress VEGFinduced cell proliferation, hRMVECs were stimulated with VEGF [30 ng/ml] for 48 hours and DNA content was evaluated

  • VEGF165 induced a significant increase in hRMVECs proliferation, by 70.8% 60.1% [***P,0.001], as compared to cells that were cultured in the absence of VEGF [medium only] [Fig. 1B]

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Summary

Introduction

Angiogenesis is the formation of new blood vessels and capillary beds from existing vessels, which plays a fundamental role in physiological and pathological processes. Ischemia/hypoxia develops within the neovascular retina, which in turn increases VEGF levels in part through stabilization of VEGF mRNA [1]. This ischemic effect is mediated primarily by hypoxia inducible factor-1 [HIF-1], which is often considered as the master regulator of angiogenesis under ischemia/hypoxia. VEGF is one of the central angiogenic factors induced in the neovascular retina, other growth factors may play crucial roles in the development and progression of retinal NV, many of which are hypoxia-independent.

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