Peroxisome Proliferator-Activated Receptor α Deficiency Induces Vascular Pathologies through Endothelial Senescence...

This study evaluated the function of peroxisome proliferator-activated receptor α (PPARα) in vascular endothelial cells (ECs) under physiological and disease conditions. Vascular density and avascular area were evaluated in Griffonia simplicifolia isolectin B4-stained retinas. Endothelial progenitor cells were quantified using flow cytometry. Vascular leakage was evaluated by Evans Blue. The mitochondrial function and morphology were evaluated by a Seahorse analyzer and immunofluorescence staining. Cell senescence was assessed by a senescence-associated β-galactosidase activity assay and Western blot analysis. A significant reduction in the retinal vessel length and vascular mesh density was found in EC-specific PPARα conditional knockout (PPARα^ECKO) mice. Relative to PPARa^flox-KO mice with oxygen-induced retinopathy (OIR), PPARα^ECKO OIR retina showed enlarged avascular areas and decreased endothelial progenitor cell number, whereas EC-specific PPARα conditional transgenic mice showed reduced avascular areas in the OIR retina. Compared with diabetic PPARa^flox-KO mice, diabetic PPARα^ECKO mice showed declined electroretinographic amplitudes, decreased retinal thickness, and increased retinal vascular leakage. PPARα deficiency exacerbated, whereas PPARα activation alleviated, EC mitochondrial dysfunction induced by diabetic stressors. PPARα^-/- ECs developed senescence, prominent oxidant-induced mitochondria fragmentation, and down-regulation of translocase of outer mitochondrial membrane 20 and peroxisome proliferator-activated receptor γ coactivator 1α, relative to wild-type ECs. These results suggest that PPARα in microvascular ECs regulates retinal vascular development and protects ECs against diabetes/hypoxia-induced vascular dysfunction through mitochondrial protective and anti-senescence activities.