Post-stroke cognitive impairment (PSCI) is a leading VCID with no treatments. While it is known that proper cerebrovascular function is critical for brain health, our poor understanding of the cellular/molecular mechanisms that promote the onset and progression of cognitive decline at the vascular unit (VU)/neuron interface limited the identification of therapeutic targets. Inadequate inclusion of vascular risk factors, biological sex and long- term stroke care practices into the recovery research prevented the development of comprehensive preventive and therapeutic strategies for PSCI. The goal of this proposal is to address these gaps in knowledge by advancing our understanding of the role of the endothelin (ET) system beyond its extensively studied contractile effects to the regulation of the VU (endothelial cell-pericyte-astrocyte) integrity using preclinical models of hypertension, PSCI and rehabilitation. Brain ET-1 levels correlate with the degree of hypoperfusion and the severity of dementia. Yet, how and to what extent the ET system contributes to PSCI is not known. In contrast to the detrimental effects of ETA receptor (ETAR) signaling, the encouraging results of a recently completed Phase III trial showed that the stimulation of ETBR improves functional outcomes. We have evidence that prevention of cognitive decline is associated with preserved VU integrity; integration of enriched care (EnCare) with social/physical activities to our stroke care paradigm attenuates PSCI in male SHRs; this is associated with the prevention of stroke-induced increases in the expression of VU ETAR, brain microvascular endothelial cells (BMVECs), which were previously thought to have only ETBR, also possess ETAR, and ETAR signaling promotes BMVEC and pericyte degeneration (senescence, endothelial mesenchymal transition-EndMT, and transition of pericytes to a microglia-like phenotype). We hypothesize that dysregulation of microvascular ETAR/ETBR balance contributes to profound progressive PSCI in hypertension by promoting degeneration of the VU which disrupts vaso-neuronal coupling. A corollary to this hypothesis is that modulation of the ET signaling via ETAR blockade or ETBR stimulation will improve the functional and structural integrity of the VU and prevent PSCI. Aim 1 will determine the relationship of post-stroke changes in the ET system with the development of PSCI. Mechanistic Aim 2 will determine endothelial yin-yang (ETAR-ETBR) mechanisms contributing to the regulation of VU phenotypes and vasotrophic (un)coupling by defining the impact of modulation of the ETAR or ETBR signaling on autocrine/paracrine regulation of senescence and phenotypes of VU cells in and targeted eETAR silencing on VU integrity and PSCI. Translational Aim 3 will determine the most effective approaches to stimulate protective ETR signaling by defining the impact of intranasal or systemic administration of ETAR antagonist BQ123 or ETBR agonist IRL-1620 alone and in combinatio...