Peroxisome Proliferator-Activated Receptor α Deficiency Induces Vascular Pathologies through Endothelial Senescence in Diabetic Retinopathy

This study evaluated the function of PPARα in vascular endothelial cells (EC) under physiological and disease conditions. EC-specific PPARα conditional knockout ( PPARα ECKO ) and transgenic ( PPARα ECTG ) mice were generated. Retinal vascular density and avascular area were evaluated in Griffonia simplicifolia isolectin B4 stained retinas. Endothelial progenitor cells (EPC) were quantified using flow cytometry. Vascular leakage in streptozotocin-induced diabetic animals was evaluated by Evans Blue. The mitochondrial function and morphology were evaluated by a Seahorse XF Pro analyzer and immunofluorescent staining. Cell senescence was assessed by an SA-β-gal activity assay and P21 expression. A significant reduction in the retinal vessel length and vascular mesh density was found in PPARα ECKO mice. Relative to PPARa flox-KO mice with oxygen-induced retinopathy (OIR), PPARα ECKO OIR retina showed enlarged avascular areas and decreased EPC number, while PPARα ECTG mice showed reduced avascular areas in the OIR retina. Compared to diabetic PPARa flox-KO mice, diabetic PPARα ECKO mice showed declined ERG amplitudes, decreased retinal thickness and increased retinal vascular leakage. PPARα deficiency exacerbated, while PPARα activation alleviated mitochondrial dysfunction in EC exposed to diabetic stressors. PPARα -/- EC developed senescence, prominent oxidant-induced mitochondria fragmentation and downregulation of TOMM20 and PGC-1α, relative to wild-type EC. These results suggest that PPARα in microvascular EC regulates retinal vascular development and protects EC against diabetes/hypoxia-induced vascular dysfunction through mitochondrial protective and anti-senescence activities.