Vascular basement membrane laminins modulate functional zonation of cerebral microvessels

We investigated whether basement membrane (BM) laminins influence regional differences in the vasculature by performing single-cell RNA sequencing on cerebral blood vessels from mice lacking the major vascular laminins in endothelial and smooth muscle BMs, laminin α4 ( Lama4 −/− ) and laminin α5 ( Tek-cre:Lama5 −/− ), and wild-type littermates. Our dataset expands existing cerebral vascular transcriptomic profiles and reveals that Lama4 −/− endothelial cells exhibit increased arterial marker expression and reduced postcapillary venule identity. In vitro and in vivo studies indicated that compensatory upregulation of laminin α5 in Lama4 −/− vessels enhances expression of junctional proteins ( Ocln , Cldn5 ) and promotes vessel contractility via increased expression of contractile molecules in mural cells. Additionally, loss of Lama4 upregulated expression of large artery markers ( Gja4 , Dll4 , Tgfb2 ) and resulted in elevated autotaxin ( Enpp2 ) levels, a key enzyme in lysophosphatidic acid production implicated in stroke. Accordingly, Lama4 −/− mice exhibited worsened stroke outcomes, driven not by immune infiltration or junctional defects, but by increased vascular permeability likely mediated by autotaxin and/or activation of resident myeloid cells. Our data suggest that laminin α4/α5 ratios in vascular BMs affect functional zonation between arterioles, capillaries and postcapillary venules by modulating metabolic pathways in endothelial and mural cells, and indirectly influencing resident myeloid cells.