EXPRESS: Reperfusion-sensitive induction of endothelial NDRG1 identifies a dynamic vascular stress response to thrombolysis in ischemic stroke.

Abstract

Ischemic stroke (IS) outcome critically depends on the neurovascular unit's capacity to respond to ischemia-reperfusion stress within the salvageable penumbra. Here, we characterize the spatiotemporal regulation of N-myc downstream-regulated gene 1 (NDRG1) and identify it as an early, reperfusion-sensitive marker of endothelial stress. Under physiological conditions, NDRG1 is primarily expressed in neurons and oligodendrocytes, with minimal endothelial expression. Following middle cerebral artery occlusion, NDRG1 undergoes marked spatial and cellular redistribution, becoming strongly induced in endothelial cells across the cerebrovascular tree.Endothelial NDRG1 induction was detectable as early as 6 hours after ischemia and evolved from a vesicular pattern to diffuse vascular labeling by 24 hours. Importantly, recombinant tissue-type plasminogen activator (rtPA) selectively enhanced endothelial NDRG1 expression in peri-lesional vessels in the rtPA-sensitive thrombin model, but not in the rtPA-resistant FeCl₃ model, indicating that NDRG1 induction is linked to effective reperfusion. In vitro, oxygen-glucose deprivation (OGD) recapitulated endothelial NDRG1 induction, further enhanced by rtPA through a pathway involving the LDL receptor family.Collectively, these findings identify endothelial NDRG1 as a dynamic molecular readout of reperfusion-sensitive vascular stress. NDRG1 may serve as a biomarker of endothelial responsiveness to thrombolytic therapy, providing new insight into cerebrovascular adaptations associated with successful reperfusion.