Abstract
At the blood-brain barrier (BBB), laminin-α5 is predominantly synthesized by endothelial cells and mural cells. Endothelial laminin-α5 is dispensable for BBB maintenance under homeostatic conditions but inhibits inflammatory cell extravasation in pathological conditions. Whether mural cell-derived laminin-α5 is involved in vascular integrity regulation, however, remains unknown. To answer this question, we generated transgenic mice with laminin-α5 deficiency in mural cells (α5-PKO). Under homeostatic conditions, no defects in BBB integrity and cerebral blood flow (CBF) were observed in α5-PKO mice, suggesting that mural cell-derived laminin-α5 is dispensable for BBB maintenance and CBF regulation under homeostatic conditions. After ischemia-reperfusion (MCAO) injury, however, α5-PKO mice displayed less severe neuronal injury, including reduced infarct volume, decreased neuronal death, and improved neurological function. In addition, α5-PKO mice also showed attenuated vascular damage (milder BBB disruption, reduced inflammatory cell infiltration, decreased brain edema, and diminished hemorrhagic transformation). Mechanistic studies revealed less severe tight junction protein (TJP) loss and pericyte coverage reduction in α5-PKO mice after ischemia-reperfusion injury, indicating that the attenuated ischemic injury in α5-PKO mice is possibly due to less severe vascular damage. These findings suggest that mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke and that inhibiting its signaling may have a neuroprotective effect.
Highlights
The blood-brain barrier (BBB) is a dynamic structure mainly composed of brain microvascular endothelial cells (BMECs), pericytes, astrocytes, and a non-cellular component---the basement membrane (BM) [7, 57, 77]
In the experimental autoimmune encephalomyelitis (EAE) model, decreased T cell infiltration into the brain and reduced disease susceptibility & severity were observed in laminin-α4 null mice [73], which exhibited compensatory and ubiquitous expression of laminin-α5 along the vasculature [73]. These findings suggest that endothelial laminin-α5 plays an inhibitory role in inflammatory cell extravasation under pathological conditions, it is dispensable for BBB maintenance under physiological conditions [25, 63]
We investigated the functions of mural cell-derived laminin-α5 in BBB regulation under homeostatic conditions and in ischemic stroke
Summary
The blood-brain barrier (BBB) is a dynamic structure mainly composed of brain microvascular endothelial cells (BMECs), pericytes, astrocytes, and a non-cellular component---the basement membrane (BM) [7, 57, 77]. The BM consists of highly organized extracellular matrix proteins synthesized by astrocytes, BMECs, and mural cells, which include both pericytes and vascular smooth muscle cells (vSMCs) [29, 51, 67, 76]. The major cell types that synthesize laminin-α5 in the vasculature are BMECs and mural cells [26, 29, 46, 62, 65, 67, 80]. In collagenase-induced intracerebral hemorrhage (ICH) model, these mutants displayed exacerbated inflammatory cell infiltration
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