Abstract TMP102: Loss of Laminin-α5 From Mural Cells Attenuates Ischemia-reperfusion Injury

Abstract

Introduction: Laminin-α5, a major component of the basement membrane, participates in embryogenesis and vascular maturation. In the vasculature, laminin-α5 is predominantly synthesized by brain microvascular endothelial cells and mural cells. With distinct laminin β and γ chains, these cells make different α5-containing laminin isoforms. It has been shown that although dispensable for blood-brain barrier (BBB) maintenance under homeostatic conditions, endothelial laminin-α5 actively regulates inflammatory cell infiltration into the brain in pathological conditions. The function of mural cell-derived laminin-α5, however, remains unknown. Here, we investigated the roles of mural cell-derived laminin-α5 in BBB maintenance under homeostatic conditions and disease progression/outcome in ischemic stroke. Methods: Laminin-α5 flox/flox mice were crossed with the Pdgfrβ-Cre + transgenic line to generate mural cell-specific laminin-α5 deficient mice (α5-PKO). BBB permeability and cerebral blood flow were measured in α5-PKO mice and their littermate controls under homeostatic conditions. In addition, these mice were subjected to 45 minutes of middle cerebral artery occlusion followed by reperfusion. At various time points after injury, brain infarct volume,neurologicalfunction, body weight loss, neuronal death, brain edema, BBB integrity, inflammatory cell extravasation, and hemorrhagic transformation were examined. Results: Comparable BBB integrity and cerebral blood flow were found in control and α5-PKO mice under homeostatic conditions. After ischemia-reperfusion injury, α5-PKO mice displayed smaller infarct volume, improved neurological function, attenuated body weight loss, reduced neuronal death, decreased brain edema, ameliorated BBB disruption, diminished inflammatory cell infiltration, and less severe hemorrhagic transformation. Conclusions: These results demonstrate that mural cell-derived laminin-α5 is dispensable for BBB maintenance and cerebral blood flow under homeostatic conditions, and that α5-PKO mice are profoundlyresistant to ischemic stroke, possibly through enhanced vascular integrity. These findings highlight a detrimental role of mural cell-derived laminin-α5 in ischemic stroke.