Loss of Endothelial YAP/TAZ Reduces the Size of Chronic Stroke Lesions and Alters the Endothelial Environment.

BACKGROUND: Ischemic stroke remains a leading cause of morbidity and mortality worldwide, with limited treatment options available. Vascular dysfunction is a key pathomechanism, and brain endothelial cells (bECs) play a critical role in determining stroke outcomes. This study investigates the specific roles of YAP (yes-associated protein 1) and TAZ (WW domain containing transcription regulator 1) in regulating bEC functions during stroke. METHODS: Mice underwent 30-minute middle cerebral artery occlusion (MCAo) followed by reperfusion to model ischemic stroke. TAZ reporter mice were used to track stroke-induced subcellular changes in TAZ expression. Tamoxifen-inducible endothelial-specific Yap/Taz knockout and control mice were used to study YAP/TAZ's role in bEC function post-stroke. Stroke outcomes were measured by magnetic resonance imaging and NeuN (neuronal nuclei)-associated lesion analysis. Properties of bECs were assessed via immunohistochemistry and RNA sequencing. Inflammatory parameters were analyzed by flow cytometry of brain immune cells and quantitative polymerase chain reaction. RESULTS: Middle cerebral artery occlusion/reperfusion regulated Yap, Taz, and YAP/TAZ target gene expression in the brain. TAZ reporter mice confirmed stroke-induced endothelial YAP/TAZ activation. Endothelial-specific loss of YAP/TAZ reduced infarct volumes at 4 weeks after MCAo without impairing stroke-induced angiogenesis, revealing an unexpected neuroprotective role for endothelial YAP/TAZ depletion. YAP/TAZ deficiency modulated cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) and Wnt (wingless-related integration site) signaling genes in bECs and promoted myeloid cell recruitment and an anti-inflammatory vascular environment during the subacute phase of stroke. CONCLUSIONS: Our data suggest that endothelial YAP/TAZ affects the inflammatory milieu subacutely after ischemia and thereby influences the chronic course of stroke. Modulation of YAP/TAZ activity in ECs may be a promising therapeutic target to promote neuroprotection after stroke.