Nitro‐oleic acid activation of endothelial PPARγ signaling pathway alleviates neurovascular injury and improves functional outcomes in ischemic stroke

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Abstract
Nitro‐oleic acid (OA‐NO 2 ) is an endogenous peroxisome proliferator‐activated receptor‐γ (PPARγ) ligand and can activate this receptor under both physiological and pathological conditions. In this study, we explore the role and molecular mechanisms of OA‐NO 2 in maintaining blood–brain barrier (BBB) integrity and enhancing neurovascular function during ischemic stroke, with a particular emphasis on the activation of endothelial PPARγ signaling pathways. Endothelial cell‐selective PPARγ conditional knockout (EC‐PPARγ cKO) and wild‐type (WT) mice underwent 1 h middle cerebral artery occlusion (MCAO) with 1–7 days of reperfusion. Mice were treated with oleic acid (OA) or OA‐NO 2 (5 mg/kg) via tail vein 2 h after MCAO. Neurobehavioral deficits were assessed on days 3, 5, and 7 after MCAO. Neuroinflammation and BBB function were assessed on days 1 or 2 after MCAO by immunohistochemistry, RT‐qPCR, or Western blot analysis. Compared to OA controls, intravenous administration of OA‐NO 2 led to reduced BBB leakage in ischemic brains, as indicated by a significant decrease in the extravasation of BBB tracers. This reduction in BBB leakage was also almost abolished in the EC‐PPARγ cKO mice. Furthermore, OA‐NO 2 treatment reduced brain infarction in stroke mice, but this protective effect was completely reversed in the EC‐PPARγ cKO mice. Interestingly, OA‐NO 2 treatment promoted a shift towards an anti‐inflammatory microglial phenotype (M2) in the peri‐infarct regions of WT mice, but not in EC‐PPARγ cKO mice. Mechanistically, OA‐NO 2 increased levels of major endothelial tight junction proteins in WT mice but not in EC‐PPARγ cKO mice following ischemic stroke. These findings suggest that OA‐NO 2 activation of endothelial PPARγ signaling cascade attenuates neurovascular injury after ischemic stroke.
Funding Information
  • VA Pittsburgh Healthcare System (I01BX004837, I01BX005750)
  • National Institutes of Health (R01NS131122, R01NS136154)
  • American Heart Association (23TPA1068534)

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