The Expanding Cell Diversity of the Brain Vasculature

Abstract

The cerebrovasculature is essential to brain health and is tasked with ensuring adequate delivery of oxygen and metabolic precursors to ensure normal neurologic function. This is coordinated through a dynamic, multi-directional cellular interplay between vascular, neuronal, and glial cells. Molecular exchanges across the blood-brain barrier or the close matching of regional blood flow with brain activation are not uniformly assigned to arteries, capillaries, and veins. Evidence has supported functional segmentation of the brain vasculature. This is achieved in part through morphologic or transcriptional heterogeneity of brain vascular cells-including endothelium, pericytes, and vascular smooth muscle. Advances with single cell genomic technologies have shown increasing cell complexity of the brain vasculature identifying previously unknown cell types and further subclassifying transcriptional diversity in cardinal vascular cell types. Cell-type specific molecular transitions or zonations have been identified. In this review, we summarize emerging evidence for the expanding vascular cell diversity in the brain and how this may provide a cellular basis for functional segmentation along the arterial-venous axis.

Keywords: astrocytes; blood brain barrier; endothelial cells; neurovascular unit; pericytes and vascular smooth muscle cells; perivascular fibroblasts; perivascular macrophages; single cell sequencing.

FIGURE 1

Brain vascular cell diversity along the arterial-venous axis. (A) Large arteries (red) and cortical veins (blue) course within the subarachnoid space (gray mesh) inside the dura mater (gray). Cerebral arteries course along the brain’s pial surface and within sulci giving rise to pial and penetrating arterioles which pierce the brain parenchyma. (B) Arterioles progressively branch to form capillaries. Capillaries then converge to form venules which converge further to form veins. Each vessel segment along the arterial-venous axis are comprised of different cell types—including endothelium (shown in red, gray, and blue to denote transcriptional zonations), vascular smooth muscle cells (dark gray, vSMCs), pericytes (green), perivascular fibroblasts (yellow), and perivascular macrophages (light blue). Pericytes further adopt different morphologic configurations along the arteriovenous axis, such as ensheathing pericytes (pre-capillary arterioles) and mesh-like and stellate pericytes in more distal arterioles, capillaries, and venules. vSMCs form concentric rings in arteries but are discrete and stellate shaped in veins. Perivascular fibroblasts and macrophages are found in arteries, arterioles, venules, and veins, but not capillaries. (C–E) Cross section of cellular components of artery (C), capillary (D), and veins (E). Endothelium depicted in artery, capillary, and vein are shown in red, light gray, and blue, respectively, to denote transcriptional differences or molecular zonations defined and validated by independent groups with single cell RNA-sequencing. Dark gray, vascular smooth muscle cells; Navy blue, internal elastic lamina; Green, pericytes; Orange, perivascular fibroblasts; Light blue, perivascular macrophages; Yellow, basement membrane; Purple, astrocyte end feet.