The effects of hypertension on the cerebral circulation

Abstract

Maintenance of brain function depends on a constant blood supply. Deficits in cerebral blood flow are linked to cognitive decline, and they have detrimental effects on the outcome of ischemia. Hypertension causes alterations in cerebral artery structure and function that can impair blood flow, particularly during an ischemic insult or during periods of low arterial pressure. This review will focus on the historical discoveries, novel developments, and knowledge gaps in 1) hypertensive cerebral artery remodeling, 2) vascular function with emphasis on myogenic reactivity and endothelium-dependent dilation, and 3) blood-brain barrier function. Hypertensive artery remodeling results in reduction in the lumen diameter and an increase in the wall-to-lumen ratio in most cerebral arteries; this is linked to reduced blood flow postischemia and increased ischemic damage. Many factors that are increased in hypertension stimulate remodeling; these include the renin-angiotensin-aldosterone system and reactive oxygen species levels. Endothelial function, vital for endothelium-mediated dilation and regulation of myogenic reactivity, is impaired in hypertension. This is a consequence of alterations in vasodilator mechanisms involving nitric oxide, epoxyeicosatrienoic acids, and ion channels, including calcium-activated potassium channels and transient receptor potential vanilloid channel 4. Hypertension causes blood-brain barrier breakdown by mechanisms involving inflammation, oxidative stress, and vasoactive circulating molecules. This exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline, and impaired recovery from ischemia. As the population ages and the incidence of hypertension, stroke, and dementia increases, it is imperative that we gain a better understanding of the control of cerebral artery function in health and disease.

Keywords: artery remodeling; cerebral vasculature; hypertension.

Figures

Fig. 1.

A: large cerebral arteries and the circle of Willis. B: cross-sectional representation of a segment of the cerebral circulation including the perivascular nerves. Extrinsic innervation of the vessels at the surface of the brain comes from the peripheral nervous system (PNS), nerves originate in the superior cervical (SCG), sphenopalatine (SPG), or otic (OG) or trigeminal (TG) ganglion. Arteries within the brain parenchyma, or the microcirculation, receive intrinsic inniveration; these nerves originate in the central nervous system (CNS). Cortical microvessels receive norepinephrine (NA), serotonin (5-HT), acetylcholine (ACh), or GABAergic afferents from subcortical neurons from the locus coeruleus, raphe nucleus, basal forebrain, or local cortical interneurons. Inset: neurovascular unit, which consists of the vascular endothelium, and smooth muscle cells or pericytes, astroglia, and neurons. CGRP, calcitonin gene-related peptide; GABA, γ-aminobutyric acid; NKA, neurokinin A; NOS, nitric oxide (NO) synthase; NPY, neuropeptide Y; PACAP, pituitary adenylate-cyclase activating polypeptide; SOM, somatostatin; SP, substance P; VIP, vasoactive intestinal polypeptide. Reproduced from Hamel (83) with permission.

Fig. 2.

Cerebral blood flow in relation to artery lumen diameter. Dotted lines represent the lower and upper limits of cerebral blood flow autoregulation. Red circles represent the cerebral arteries, and blue line represents the cerebral blood flow. Modified from Mangat (129); used with permission.

Fig. 3.

Recent advances in cerebral artery function. Five major recent findings are summarized: 1) transient receptor potential vanilloid 4 (TRPV4) channels in endothelial cells (ECs) and are coupled to muscarinic receptor activation and generate a calcium sparklet, which opens intermediate-conductance and small-conductance Ca2+-activated K+ channels (IKCa and SKCa, respectively), leading to K+ efflux and hyperpolarization. The hyperpolarization is then transmitted to smooth muscle cells (SMCs) through myoendothelial junction. It is still unknown whether this system is present in ECs of cerebral arteries and how hypertension might affect it (question mark in the figure); 2) pleiotropic effects of drugs: cilostazol, an antiplatelet drug, improves endothelial function in hypertensive rats by increasing phosphorylation of the endothelial NOS (eNOS), the active form of this enzyme. Resveratrol, an antioxidant, also increases eNOS function. The net result is an increase in NO bioavailability, which is known to be reduced in hypertensive EC (blue); 3) epoxyeicosatrienoic acids (EETs) are arachidonic acid (AA) metabolites that cause cerebral artery dilation. EETs activate TRPV4 channels that allow for a small calcium influx that opens ryanodine receptors (RyRs) in the sarcoplasmic reticulum. RyR causes a local and transient increase in intracellular calcium, a calcium spark, which opens large-conductance Ca-activated K+ channels (BKCa), leading to efflux of K+ and hyperpolarization. The soluble epoxide hydrolase (sEH) inactivates EETs to dihydroxyeicosatrienoic acids (DHETs) and may be increased in hypertension (red); 4) many vasoactive peptides, including angiotensin II and endothelin-1, increase the activity of the enzyme NADPH oxidase, causing accumulation of superoxide anion. Superoxide can be dismutated into hydrogen peroxide by the superoxide dismutase enzyme (SOD), or it can react with NO, blunting NO availability. Paradoxically, SOD expression is increased in hypertension, possibly leading to increased hydrogen peroxide production. Hydrogen peroxide activates Ca2+ sparks and BKCa in SMCs, and it is possible that it accomplished that through activation of TRPV4 channels; 5) transient receptor potential 3 (TRPC3) channels, found exclusively in SMCs, are overexpressed in hypertensive carotid arteries and are involved in the vasoconstriction caused by UTP. Opening of TRPC3 channels causes a localized depolarization that opens L-type Ca2+ channels, leading to SMC depolarization and vasoconstriction. Cyp, cytochrome P-450; RAAS, renin-angiotensin-aldosterone system.