Endothelial β4 Integrin Is Predominantly Expressed in Arterioles, Where It Promotes Vascular Remodeling in the Hypoxic Brain

Abstract

Laminin is a major component of the vascular basal lamina, implying that laminin receptors, such as α6β1 and α6β4 integrins, may regulate vascular remodeling and homeostasis. Previous studies in the central nervous system have shown that β4 integrin is expressed by only a fraction of cerebral vessels, but defining the vessel type and cellular source of β4 integrin has proved controversial. The goal of this study was to define the class of vessel and cell type expressing β4 integrin in cerebral vessels and to examine its potential role in vascular remodeling. Dual-immunofluorescence showed that β4 integrin is expressed predominantly in arterioles, both in the central nervous system and in peripheral organs. Cell-specific knockouts of β4 integrin revealed that β4 integrin expression in cerebral vessels is derived from endothelial cells, not astrocytes or smooth muscle cells. Lack of endothelial β4 integrin had no effect on vascular development, integrity, or endothelial proliferation, but in the hypoxic central nervous system, its absence led to defective arteriolar remodeling and associated transforming growth factor-β signaling. These results define high levels of β4 integrin in arteriolar endothelial cells and demonstrate a novel link among β4 integrin, transforming growth factor-β signaling, and arteriolar remodeling in cerebral vessels.