Brain vascular heterogeneity: implications for disease pathogenesis and design of in vitro blood-brain barrier models

Abstract

The vertebrate blood-brain barrier (BBB) is composed of cerebral microvascular endothelial cells (CEC). The BBB acts as a semi-permeable cellular interface that tightly regulates bidirectional molecular transport between blood and the brain parenchyma in order to maintain cerebral homeostasis. The CEC phenotype is regulated by a variety of factors, including cells in its immediate environment and within functional neurovascular units. The cellular composition of the brain parenchyma surrounding the CEC varies between different brain regions; this difference is clearly visible in grey versus white matter. In this review, we discuss evidence for the existence of brain vascular heterogeneity, focusing on differences between the vessels of the grey and white matter. The region-specific differences in the vasculature of the brain are reflective of specific functions of those particular brain areas. This BBB-endothelial heterogeneity may have implications for the course of pathogenesis of cerebrovascular diseases and neurological disorders involving vascular activation and dysfunction. This heterogeneity should be taken into account when developing BBB-neuro-disease models representative of specific brain areas.

Keywords: Blood–brain barrier; Cerebral vasculature; Grey matter; In vitro models; Neurodegeneration; Neurovascular unit; White matter.

Fig. 1

General representation of structural and cellular differences between GM and WM: the brain is approximately segmented in equal volumes of GM and WM, where the cellular composition differs considerably. GM has a high non-myelinated neuronal content and lesser extent of myelinated axons. WM is composed of both myelinated and non-myelinated axons; with higher myelin content is responsible for its whitish appearance. Similarly, GM and WM also exhibit differences in other resident brain cell types, including astrocytes, glial cells in number and morphology. These differences in the immediate environment of the vasculature may confer specific differential WM and GM vascular phenotypes that may be reflected in amount and organization of tight junctions, expression of various receptors, transporters and responses to stimuli in neurovascular diseases