Loss of laminin-γ1 in pericytes impairs microvascular function and cognition

Blood-brain barrier (BBB) disruption correlates with lesion burden and cognitive dysfunction in cerebral small vessel disease (CSVD). Laminin, highly produced by pericytes in the brain, maintains BBB integrity. However, it remains unclear if laminin dysregulation contributes to the pathogenesis of CSVD. Here, we show that mice lacking laminin-γ1 in pericytes, smooth muscle cells, and fibroblasts (PKO) develop age-dependent BBB disruption via both paracellular and transcellular mechanisms. In contrast, loss of laminin-γ1 in smooth muscle cells or fibroblasts fails to affect BBB integrity. In addition, the PKO mice exhibit pericyte loss, thickened basal lamina, increased brain stiffness, followed by brain clearance defect, synaptic loss, and cognitive impairment. Together, these results demonstrate that loss of pericytic laminin-γ1 induces progressive vascular dysfunction and several features of CSVD, including brain stiffness, synaptic loss, and cognitive impairment, highlighting a potential role of laminin-γ1 dysregulation in the pathogenesis of CSVD.