Loss of Pericytic Integrin-β1 Exacerbates Blood-Brain Barrier Damage and Hemorrhagic Brain Injury.

Abstract

Pericytes play essential roles in blood-brain barrier regulation and stroke pathogenesis. Given that pericytes are embedded in the ECM (extracellular matrix), it is speculated that ECM-receptor interactions are involved in these functions. Integrin-β1, the most common integrin subunit that can engage multiple ECM proteins, is highly expressed in pericytes. The function of pericytic integrin β1, however, remains unknown. To address this question, we generated brain pericyte-specific integrin-β1 knockout mice by crossing the Atp13a5-CreER with the Itgb1 floxed mice and characterized their phenotypes under homeostatic conditions and after intracerebral hemorrhage. Under homeostatic conditions, pericyte-specific integrin-β1 knockout mice were grossly normal and failed to show blood-brain barrier disruption or pericyte/astrocyte defects. In the collagenase-induced intracerebral hemorrhage model, however, the pericyte-specific integrin-β1 knockout mice exhibited larger hematoma volume, enhanced brain edema, aggravated blood-brain barrier damage caused by both paracellular and transcellular mechanisms, reduced pericyte number/coverage and AQP4 coverage, increased neuronal death, elevated gliosis, and worsened neurological outcomes. Interestingly, hypertensive pericyte-specific integrin-β1 knockout mice demonstrated similar changes in the autologous blood model of intracerebral hemorrhage. These results suggest that brain pericyte-derived integrin-β1 is dispensable under homeostatic conditions but plays a protective role in intracerebral hemorrhage, likely through repairing blood-brain barrier damage and regulating gliosis.