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Activin A prevents hyper-responsiveness to VEGF in pathological blood vessels by perturbing trafficking of activated VEGFR2

ABSTRACT: While quality of life compromising afflictions such as diabetic retinopathy (DR) are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Activin A (activin), a ligand of the transforming growth factor β superfamily (TGF-β), attenuated VEGF-induced VE-cadherin disorganization, pore formation and permeability of primary human retinal endothelial cells (HRECs). Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally-localized protein tyrosine phosphatase, (PTP1b), whereas PTPs present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 (VEGFR2) at time points 30 min and longer post stimulation. Together these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGFR2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathological blood vessels from patients who developed end-stage proliferative diabetic retinopathy (PDR). This defect rendered HRECs hyper-responsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights regarding the pathogenesis of PDR in patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291008 | GEO | 2025/06/03

REPOSITORIES: GEO

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Project description:Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of visual impairment and blindness in people aged 50 years or older in middle-income and industrialized countries. Anti-VEGF therapies have improved the management of neovascular AMD (nAMD) and proliferative DR (PDR), no treatment options exist for the highly prevalent dry form of AMD. To unravel the biological processes underlying these pathologies and to find new potential biomarkers, a label-free quantitative (LFQ) method was applied to analyze the vitreous proteome in PDR (n=4), AMD (n=4) compared to idiopathic epiretinal membranes (ERM) (n=4). Post-hoc tests revealed 96 proteins capable of differentiating among the different groups, whereas 118 proteins were found differentially regulated in PDR compared to ERM and 95 proteins in PDR compared to dry AMD. The pathway analysis indicates that mediators of complement and coagulation cascades and acute phase responses are enriched in PDR vitreous, whilst proteins highly correlated to the extracellular matrix (ECM) organization, platelet degranulation, lysosomal degradation, cell adhesion, and central nervous system development were found underexpressed. According to these results, 35 proteins were selected and validated by MRM (multiple reaction monitoring) in a larger cohort of patients with ERM (n=21), DR/PDR (n=20), AMD (n=11), and retinal detachment (n=13). Of these, 26 proteins were validated and were capable of differentiating between vitreoretinal diseases under study. Based on Partial least squares discriminant and multivariate exploratory receiver operating characteristic (ROC) analyses, a panel of 15 discriminatory biomarkers was defined, which includes complement and coagulation components (CO2 and prothrombin), acute-phase mediators (alpha-1-antichymotrypsin), adhesion molecules (e.g., myocilin, galectin-3-binding protein), ECM components (opticin), and neurodegeneration biomarkers (beta-amyloid, amyloid-like protein 2).

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Activin A prevents hyper-responsiveness to VEGF in pathological blood vessels by perturbing trafficking of activated VEGFR2

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