The contribution of endothelial basement membrane laminins and immune cells to functional integrity of the neurovascular unit

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The functional connection between blood vessels in the brain and the surrounding neurons is illustrated by the rapid response of neurons to focal ischemia, and is manifested by endothelial cells, astrocytes and neurons, but also two distinct basement membranes (BMs) that underlie the endothelium and marker the border to the CNS parenchyma (known as the endothelial and parenchymal BMs, respectively). These cellular and acellular layers collectively form a structural continuum between blood vessel and neurons that is now commonly referred to as the neurovascular unit (NVU). While the cellular constituents of the NVU are common topics of research, the BMs of the NVU and their contribution to its structural and functional integrity are poorly understood. We have shown that the endothelial and parenchymal BMs are biochemically distinct, varying principally in their laminin isoforms composition, with laminin alpha4 and alpha5 characterising the endothelial BM and laminin alpha2 and alpha1 characterizing the parenchymal BM. Neuroinflammation studies in our lab have also shown that the two BMs impact differently on leukocyte extravasation across CNS postcapillary venules, with laminin alpha5 and alpha4 acting as migration cues for infiltrating leukocytes and the parenchymal BM acting as the effective barrier to the CNS parenchyma. More recent studies using laminin alpha4 knockout (KO) mice (Lama4-/-), and endothelial cell specific laminin alpha5 conditional KO mice in transient middle cerebral artery occlusion (MCAO), an ischemic stroke model, have further implicated specifically laminin alpha5 in endothelial cell barrier properties. In addition, the MCAO studies revealed an unexpected accumulation of immune cells within vessel lumens and between BMs layers, in an as yet undefined manner, suggesting that immune cells within the vessel lumen and/or perivascular zone can communicate with the surrounding CNS parenchyma. We here propose to focus on the endothelial portion of the NVU, with emphasis on the endothelial cell BM laminins, laminin alpha4 and alpha5, and how they influence the functional integrity of the NVU. In addition, we will investigate the molecular mechanism/s of immune cell interaction with cerebral vessels following ischemic stroke. These studies will contribute to the understanding of factors important for normal NVU function and are likely to open new avenues for the development of more effective therapies to minimize brain damage after ischemic stroke.