The Evolving Concept of the Blood Brain Barrier (BBB): From a Single Static Barrier to a Heterogeneous and Dynamic Relay Center

Abstract

The blood-brain barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. The brain endothelial cells, lining the brain's vasculature, maintain close interactions with surrounding brain cells, e.g., astrocytes, pericytes and perivascular macrophages. This function facilitates critical intercellular crosstalk, giving rise to the concept of the neurovascular unit (NVU). The steady and appropriate communication between all components of the NVU is essential for normal CNS homeostasis and function, and dysregulation of one of its constituents can result in disease. Among the different brain regions, and along the vascular tree, the cellular composition of the NVU varies. Therefore, differential cues from the immediate vascular environment can affect BBB phenotype. To support the fluctuating metabolic and functional needs of the underlying neuropil, a specialized vascular heterogeneity is required. This is achieved by variances in barrier function, expression of transporters, receptors, and adhesion molecules. This mini-review will take you on a journey through evolving concepts surrounding the BBB, the NVU and beyond. Exploring classical experiments leading to new approaches will allow us to understand that the BBB is not merely a static separation between the brain and periphery but a closely regulated and interactive entity. We will discuss shifting paradigms, and ultimately aim to address the importance of BBB endothelial heterogeneity with regard to the function of the BBB within the NVU, and touch on its implications for different neuropathologies.

Keywords: blood–brain barrier; brain cellular heterogeneity; cerebral endothelial cells; neurovascular unit; vascular heterogeneity.

FIGURE 1

Heterogeneity of the neurovascular unit (NVU): current research has revealed high heterogeneity of e.g., astrocytes and pericytes within the CNS and among different brain areas. The heterogeneity of these different cellular components of the NVU in, for example, the GM (A) versus the WM (B) contributes to brain vascular heterogeneity to support local physiological and metabolic needs for that particular part of the brain. This includes differential expression of specific receptors and transporters on CECs, such as GLUT-1, Pgp and Na⁺/K⁺-ATPase, which are represented by the different shapes and colors in GM (A) versus WM-CECs (B).