Abstract P734: Reactive Astrocytes Facilitate Vascular Repair and Remodeling After Stroke

Abstract

Astrocytes and blood vessels interact closely in the neurovascular unit. After stroke, reactive astrocytes surrounding the infarct undergo structural and functional changes. Simultaneously, considerable plasticity of vascular structure occurs, including formation and elimination of microvascular segments, and is associated with restoration of blood flow and behavioral recovery. Reactive astrocytes have established protective functions soon after injury, but less is known about how they influence later reparative processes, which include vascular remodeling. Here we investigated whether reactive astrocytes support vascular remodeling in a mouse model of stroke. Analysis of gene expression data from reactive astrocytes during the first week after stroke showed substantial upregulation of genes and pathways implicated in regulating vascular and basement membrane remodeling. With repeated in vivo 2-photon imaging, we found that astrocytes contacted new vascular segments formed in peri-infarct cortex after photothrombotic infarcts, suggesting close interactions between reactive astrocytes and new blood vessels. Next, we used GFAP-thymidine kinase (TK) transgenic mice to chemogenetically ablate proliferating peri-infarct astrocytes after stroke (N=8 GFAP-TK; N=8 wildtype mice). Astrocyte ablation following photothrombotic stroke in motor cortex caused dysfunctional vascular repair and remodeling characterized by reduced vascular density, diminished endothelial cell proliferation, prolonged blood flow deficits, and sparse coverage of vessels by glycocalyx, basement membrane, and pericytes. Moreover, peri-infarct vascular permeability was exacerbated in GFAP-TK mice, and this increased permeability was correlated with heightened cell death in the subacute phase after stroke. Tests of forelimb use asymmetry and locomotor coordination both showed worsened recovery in GFAP-TK mice. In contrast to the effects of peri-infarct astrocyte ablation, vascular structure was unaffected by adeno-associated virus-mediated ablation of astrocytes in the otherwise intact brain. Our findings implicate reactive astrocytes as crucial cellular mediators of functionally important vascular repair and remodeling after stroke.