Chronic mild hypoxia increases expression of laminins 111 and 411 and the laminin receptor α6β1 integrin at the blood-brain barrier

The laminin family of glycoproteins are major constituents of the basal lamina of blood vessels, and play a fundamental role in promoting endothelial differentiation and blood-brain barrier (BBB) stability. Chronic mild hypoxia (CMH), in which mice are exposed to 8% O-2 for two weeks, induces a strong vascular remodeling response in the central nervous system (CNS) that includes endothelial proliferation, angiogenesis, arteriogenesis as well as increased expression of tight junction proteins, suggestive of enhanced vascular integrity. As previous studies highlight an important role for laminin in promoting vascular differentiation and BBB stability, the goal of this study was to determine if CMH influences the expression of the laminins and their cell surface receptors in cerebral blood vessels. Our studies revealed that over a 14 day period of CMH, blood vessels in the brain showed strong upregulation of the specific laminin subunits alpha 1 and alpha 4, corresponding to increased expression of laminins 111 and 411 respectively, with no discernible changes in the expression levels of the alpha 2 or alpha 5 laminin subunits. This was accompanied by marked endothelial upregulation of the laminin receptor alpha 6 beta 1 integrin but no alterations in the other laminin receptors at integrin or dystroglycan. In light of the instructive role for laminins in promoting vascular differentiation and stability, these data suggest that upregulation of the laminin-alpha 6 beta 1 integrin axis is part of the molecular response triggered by mild hypoxia that leads to enhanced BBB stability. (C) 2018 Elsevier B.V. All rights reserved.