Abstract
Components of the neurovascular unit (NVU) establish dynamic crosstalk that regulates cerebral blood flow and maintain brain homeostasis. Here, we describe accumulating evidence for cellular elements of the NVU contributing to critical physiological processes such as cerebral autoregulation, neurovascular coupling, and vasculo-neuronal coupling. We discuss how alterations in the cellular mechanisms governing NVU homeostasis can lead to pathological changes in which vascular endothelial and smooth muscle cell, pericyte and astrocyte function may play a key role. Because hypertension is a modifiable risk factor for stroke and accelerated cognitive decline in aging, we focus on hypertension-associated changes on cerebral arteriole function and structure, and the molecular mechanisms through which these may contribute to cognitive decline. We gather recent emerging evidence concerning cognitive loss in hypertension and the link with vascular dementia and Alzheimer’s disease. Collectively, we summarize how vascular dysfunction, chronic hypoperfusion, oxidative stress, and inflammatory processes can uncouple communication at the NVU impairing cerebral perfusion and contributing to neurodegeneration.
Highlights
Because hypertension is a modifiable risk factor for stroke and accelerated cognitive decline in aging, we focus on hypertension-associated changes on cerebral arteriole function and structure, and the molecular mechanisms through which these may contribute to cognitive decline
While the skull protects the brain from the external environment, endothelial cells are the first line of defense against the entrance of blood-borne pathogens, inflammatory-inducing components of the blood and circulating macrophages and are important contributors to brain homeostasis
Walas et al (2019) presented evidence that, prior to the onset of hypertension, cerebral arteries from the posterior circulation of 5-week-old spontaneously hypertensive rat (SHR) exhibit elevated expression of genes related to remodeling, oxidative stress, and inflammatory pathways, notably including a 40% increase in genes related to fibrosis (e.g., TGFβ)
Summary
While the skull protects the brain from the external environment, endothelial cells are the first line of defense against the entrance of blood-borne pathogens, inflammatory-inducing components of the blood and circulating macrophages and are important contributors to brain homeostasis. The brain endothelium expresses highly specialized proteins, termed adherens and tight junction proteins, that mediate tight cell-to-cell contacts These adherens (e.g., cadherins and junctional adhesion molecules) and tight junctions (e.g., occludins and claudins) contribute to formation of the blood–brain barrier (BBB), which maintains the high transendothelial electrical resistance and low paracellular transport properties characteristic of the brain endothelium (Sweeney et al, 2019; De Silva and Faraci, 2020). The cellular mechanisms that drive endothelialmediated changes in vascular tone include mechanical forces (e.g., wall shear stress), signals released by neighboring cells and electrical coupling such as endothelium-vascular smooth muscle cell (VSMC) interactions that drive hyperpolarization of the membrane potential of VSMCs, resulting in dilation (Longden et al, 2017). For a detailed review of these mechanisms (see Harraz et al, 2020)
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