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.