Shear Stress: An Underrecognized Driver of Endothelial Inflammation in Acute Ischemic Stroke.

Cerebral ischemic stroke is caused by impaired blood flow to the brain parenchyma due to acute vessel occlusion. Although current therapies focusing on rapid restoration of blood flow achieve high rates of recanalization, outcomes remain unfavorable in a significant proportion of patients. Part of this discrepancy is due to intravascular inflammation driven by thrombo-inflammatory mechanisms that add to cerebral tissue loss. Despite being an inevitable consequence of vessel occlusion, altered shear stress remains largely overlooked as a contributor to endothelial dysfunction in stroke. To directly assess the impact of disturbed flow on the endothelial phenotype, human brain endothelial cells were cultured under controlled flow conditions using an ibidi pump system and exposed to flow alternating in both magnitude and direction. Subsequently, the expression of key endothelial proteins, including Claudin-5, PECAM-1, CD62e and endoglin, was analyzed. We show here that the sequence of shear-stress modulation, recapitulating the hemodynamic conditions of large-vessel occlusion and subsequent reperfusion in stroke, is sufficient to cause an inflammatory phenotype in human brain endothelial cells. In addition, we demonstrate that platelet activation induces the mechanosensors Piezo1 and syndecan-1, sensitizing brain endothelial cells to shear-stress alterations characteristic of ischemic stroke. Targeting shear-stress-mediated inflammatory activation of the brain endothelium may therefore offer a complementary strategy in stroke therapy, particularly in large-vessel occlusion with abrupt flow changes.