Astrocytes-Mediated Regulation of Wnt/b-Catenin Pathway in Ischemic Brain

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PROJECT SUMMARY Cerebral vessel-associated astrocyte end-feet play an important role in formation and maintenance of the blood-brain barrier (BBB), and regulation of neurovascular coupling and cerebral blood flow (CBF). Ischemic stroke causes structural and biochemical changes of the perivascular astrocytes, but the underlying molecular mechanisms and subsequent impact on cerebral vessel damage/repair are not well understood. Previously, we show that in response to ischemia and hypoxia, reactive astrocytes stimulate Na+/H+ exchanger isoform 1 protein (NHE1) activity to counteract the acidic pHi. This leads to intracellular Na+ overload, astrocytic swelling, and impaired glutamate uptake, which aggravates ischemic brain damage. Our recent study shows that selective deletion of Nhe1 in astrocytes (Astro-KO) abolished ischemic stroke- mediated astrogliosis, preserved BBB function, and reduced cerebral vessel damage in a mouse model of focal ischemic stroke (transient middle cerebral artery occlusion). Despite the neuroprotective effects conferred by astrocytic Nhe1 deletion in ischemic brains, the precise molecular mechanisms involved in the process are not completely understood. Our preliminary study reveals that Wnt signaling pathway genes are the most significantly upregulated genes in Nhe1 Astro-KO ischemic brains. Most importantly, targeted deletion of Nhe1 in Astro-KO mice caused elevation of Wnt 7a/b and −catenin protein, accompanied with increased expression of tight junction protein (TJ) and preservation of TJ structures in the blood vessels after ischemic stroke. These new findings led us to hypothesize that deletion of astrocytic Nhe1 promotes ischemic tissue repair by Wnt/−catenin mediated signaling mechanisms. We will investigate that increased Wnt7a/b gene expression in Nhe1 Astro-KO mice leads to 1) increased Wnt/−catenin signaling in vascular endothelial cells, 2) improves the BBB structural and functional integrity, and 3) promotes vascular recovery by angiogenesis and restore of the cerebral flow regulation after ischemic stroke. Completion of three specific aims will generate new knowledge and identify novel therapeutic agents for promoting vascular repairs after ischemic stroke.