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.

The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction

“…Our morphological and functional understanding of the NVU, through examining the molecular composition and regional specifications of the different cell types in the CNS, has also advanced significantly. This has allowed us to begin to understand the molecular profiles of cellular components of the NVU as well as their specialization and conservation across species ( Cahoy et al, 2008 ; Roesch et al, 2008 ; Zhang et al, 2014 ; Vanlandewijck et al, 2018 ; Ross et al, 2020 ). One aspect of particular interest is to examine glia-to-EC contacts, whether this is impacted by regional specialization, and whether this and NVU function, is influenced by glia/EC identities.…”

Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

“…Intense research on the vascular landscape of areas like the choroid plexus, where a barrier more permeable than the BBB is critical to CSF production, will surely reveal new functions to the “classical” NVU cells (Liddelow, 2015 ; Lun et al, 2015 ; Kaur et al, 2016 ). These cells making up the NVU, once thought limited to ECs, astrocytes, pericytes and neurons, are also joined by “newcomers,” with perivascular fibroblasts, perivascular macrophages, resident microglia and others now believed to play an active role in cerebrovascular activity (Koizumi et al, 2019 ; Ross et al, 2020 ). With each of these cell types also displaying their own regional heterogeneity across the brain (Masuda et al, 2020 ), it is easy to imagine that even if the cerebrovascular compartment connects into one continuum, it may in fact harbor multiple somewhat distinct regions of specialized cellular composition and function.…”

“…In this regard, the development of novel neuroimaging modalities suitable for brain-wide recordings has expanded the toolset required to probe the regional heterogeneity of the NVU that was until recently mostly addressed by single cell RNA sequencing (scRNAseq) and functional magnetic resonance imaging (fMRI). The former is a major contributor in characterizing the single cell transcriptomic profile of the cellular and vascular components of the NVU highlighting region-specific differences at the brain-wide scale (Saunders et al, 2018 ; Ross et al, 2020 ) and beyond what can be achieved with conventional imaging modalities. The latter, fMRI, is a gold standard modality suitable to capture the heterogeneity of hemodynamic responses at the whole brain scale (Devonshire et al, 2012 ) and between white and gray matter (Gawryluk et al, 2014 ).…”

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

“…It is not clear when fetal endothelial cells gain similar transport properties as the adult ones ( Ek et al, 2012 ). Fully functional endothelial cells are permissive to gases, lipophilic molecules, and a subset of small molecules (<400 Da) ( Ross et al, 2020 ). Additionally, they are capable of carrier-mediated, receptor-mediated, and active transport ( Ross et al, 2020 ).…”