title: The nexus between VEGF and NFκB orchestrates a hypoxia-independent neovasculogenesis.
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.
authors.affiliation: Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. mdeniro@kkesh.med.sa
authors.forename: Michael
authors.initials: M
authors.lastname: DeNiro
authors.forename: Falah H
authors.initials: FH
authors.lastname: Al-Mohanna
authors.forename: Osama
authors.initials: O
authors.lastname: Alsmadi
authors.forename: Futwan A
authors.initials: FA
authors.lastname: Al-Mohanna
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D020536:Enzyme Activators; D007191:Indazoles; D051996:Transcription Factor RelA; D042461:Vascular Endothelial Growth Factor A; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole