Cell-specific blood-brain barrier regulation in health and disease: a focus on hypoxia

Abstract

The blood-brain barrier (BBB) is a complex vascular structure consisting of microvascular endothelial cells that line the vessel wall, astrocyte end-feet, pericytes, as well as the basal lamina. BBB cells act in concert to maintain the characteristic impermeable and low paracellular flux of the brain vascular network, thus ensuring a homeostatic neuronal environment. Alterations in BBB stability that occur during injury have dire consequences on disease progression and it is clear that BBB cell-specific responses, positive or negative, must make a significant contribution to injury outcome. Reduced oxygenation, or hypoxia, is a characteristic of many brain diseases that significantly increases barrier permeability. Recent data suggest that hypoxia-inducible factor (HIF-1), the master regulator of the hypoxic response, probably mediates many hypoxic effects either directly or indirectly via its target genes. This review discusses current knowledge of physiological cell-specific regulation of barrier function, their responses to hypoxia as well as consequences of hypoxic- and HIF-1-mediated mechanisms on barrier integrity during select brain diseases. In the final sections, the potential of current advances in targeting HIF-1 as a therapeutic strategy will be overviewed.

Keywords: BBB cell-specific response; HIF-1; astrocytes; endothelial cells; hypoxia; neurodegenerative diseases; pericytes.

Figure 1

The BBB protects neurons and glial cells from systemically circulating agents as brain microvessels form a very tight barrier clearly distinct from vessels in other organs. The barrier is formed by ECs (red), which line the blood vessels, surrounded by pericytes (light blue), BM (grey) and astrocytic (dark blue) end-feet. Astrocytes provide the cellular link to the adjacent neurons (pink). The illustration also shows microglial cells (grey) in contact with astrocytes. Inset (black box) shows the cell–cell contact that takes place between two adjacent ECs at the BBB and demonstrates the basic organization of the BBB tight and adherens junctional proteins. Note the interactions of the junctional proteins with the cytoskeleton.

Figure 2

Schematic diagram illustrating the mechanism of HIF-1 regulation under normoxic and hypoxic conditions. HIFs are heterodimeric transcription factors composed of an oxygen-sensitive α-subunit and a constitutively expressed β-subunit. Under normoxia (white gradient), the HIF-1α subunit is constitutively transcribed but constantly targeted degradation through hydroxylation of conserved proline residues by PHDs leading to recognition by VHL protein, ubiquitination and subsequent degradation by proteasome. As oxygen tension drops (red gradient), the PHD enzymes are inhibited and the lack of hydroxylation results in cytoplasmic stabilization of the α-subunits. After phosphorylation, HIF-1α translocates to the nucleus and dimerizes with HIF-1β (also known as ARNT) and co-activators such as p300/CBP forming a functional HIF-1 transcription factor. HIF-1 then binds to hypoxia-responsive elements (HREs) in the promoter regions of its many targets inducing expression of genes involved in cellular adaptation to hypoxic stress by regulating erythropoiesis, angiogenesis, proliferation and cellular metabolism in order to reduce O₂ consumption and increase O₂ delivery to tissues.

Figure 3

Flow chart of the events leading to BBB disruption and the following events occurring later in stroke, TBI and AD.