Abstract T P400: Subarachnoid Hemorrhage-Induced Reactive Astrogliosis Is Correlated With Inversion of Neurovascular Coupling

Abstract

Poor patient outcome following aneurysmal subarachnoid hemorrhage (SAH) has been linked to delayed cerebral ischemia (DCI), presenting several days following aneurysm rupture. Enhanced constriction of the brain vasculature, including intracerebral (parenchymal) arterioles contribute to SAH-induced DCI. Activity-dependent blood flow through parenchymal arterioles is controlled by local neuronal and astrocytic activity, a process known as neurovascular coupling. In response to numerous types of brain insults (e.g. tumors, trauma, and strokes), astrocytes undergo a transformation to a reactive phenotype, reactive astrogliosis, characterized by hypertrophy and hyperplasia. Here, we examined the hypothesis that SAH-induced reactive gliosis of perivascular astrocytes contribute to enhanced parenchymal arteriolar constriction. Astrocyte and vascular changes were assessed in a mouse endovascular perforation SAH model. Glial fibrillary acidic protein (GFAP), an astrocyte-specific intermediate filament that is upregulated during reactive astrogliosis, was assessed by immunohistochemistry in brain cortex of the middle cerebral artery territory. We observed increased GFAP staining at Day 2 and Day 4 following induction of SAH when compared to brain sections from control and sham-operated animals (all p values <.05). In separate animals, neurovascular coupling was examined using two-photon and infrared-differential interference contrast microscopy. In brain slices from control and sham-operated animals, neuronal activation caused the anticipated neurovascular response-an increase in astrocyte endfoot Ca2+ followed by parenchymal arteriole dilation. In marked contrast, brain slices from SAH animals exhibited an inverted neurovascular response (i.e. vasoconstriction rather than vasodilation) in ≈ 80% of brain slices from day 1 and day 2 SAH mice and ≈ 60% of slices from SAH day 4 mice. In conclusion, we demonstrate changes in astrocyte structure, the development of reactive astrogliosis, correlate to a polarity shift in neurovascular coupling after SAH. These data indicates that SAH-induced reactive astrogliosis may play an important role in DCI development.