The Effects of Obesity on the Cerebral Vasculature

Dorrance, Anne M.; Matin, Nusrat; Pires, Paulo W.

doi:10.2174/1570161112666140423222411

Cited by 80 publications

(53 citation statements)

References 129 publications

(164 reference statements)

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“…Our finding may have practical consequences; while alcohol-induced cerebral artery constriction would remain largely uncompromised, caffeine protection against alcohol would be drastically reduced under conditions that impair endothelial function and NO• availability, such as aging (Scioli et al, 2014), arterial hypertension (Hall et al, 2012), and obesity (Dorrance et al, 2014). Conversely, caffeine action against alcohol-induced vasoconstriction could be potentiated in the presence of NO• donors (as shown here from in vitro data showing SNP impacting the caffeine-18 mM ethanol interaction) that are widely used in clinical practice to treat various pathophysiologic conditions (Miller and Megson, 2007).…”

Section: Discussionmentioning

confidence: 91%

Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction

Chang

Fedinec

Kuntamallappanavar

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Despite preventive education, the combined consumption of alcohol and caffeine (particularly from "energy drinks") continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 mM) antagonized the endotheliumindependent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40-70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS 2/2 ) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 mM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without significantly disrupting endothelium-independent, alcoholinduced cerebral artery constriction itself.

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Section: Discussionmentioning

confidence: 91%

Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction

Chang

Fedinec

Kuntamallappanavar

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…; Dorrance et al . ). After T3‐SCI, the present study illustrated a decrease in MCA lumen diameter, increased wall thickness and a significant increase in wall‐to‐lumen ratio.…”

Section: Discussionmentioning

confidence: 97%

Rigid and remodelled: cerebrovascular structure and function after experimental high‐thoracic spinal cord transection

Phillips

Matin

Frias

et al. 2016

The Journal of Physiology

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Key Pointsr Spinal cord injury (SCI) is associated with a 3-4 fold increased risk of stroke, and impaired cerebral blood flow regulation, although the effect of SCI on the structure and function of the cerebral arteries is unclear.r Using pressure myography to assess isolated vessels distended at physiological pressures, we provide novel evidence that experimental SCI leads to inward cerebrovascular remodelling, increased stiffness and impaired reactivity of the largest cerebral artery.r Histochemical analyses revealed that a profibrotic environment within the largest cerebral artery occurs after SCI, which was characterized by greater collagen and less elastin. This may be due to increased transforming growth factor β, a well-known profibrotic signalling protein.r Further analysis revealed that profibrotic alterations were not due to disruption of descending sympathetic pathways to the cerebrovasculature.r Experimental SCI exerts a deleterious influence on the structure and function of cerebral arteries, which may underlie the increased risk of stroke and impaired cerebral blood flow regulation.Abstract High-thoracic or cervical spinal cord injury (SCI) is associated with several critical clinical conditions related to impaired cerebrovascular health, including: 300-400% increased risk of stroke, cognitive decline and diminished cerebral blood flow regulation. The purpose of this study was to examine the influence of high-thoracic (T3 spinal segment) SCI on cerebrovascular structure and function, as well as molecular markers of profibrosis. Seven weeks after complete T3 spinal cord transection (T3-SCI, n = 15) or sham injury (Sham, n = 10), rats were sacrificed for either middle cerebral artery (MCA) structure and function assessments via ex vivo pressure myography, or immunohistochemical analyses. Myogenic tone was unchanged, but over a range of transmural pressures, inward remodelling occurred after T3-SCI with a 40% reduction in distensibility (both P < 0.05), and a 33% reduction in vasoconstrictive reactivity to 5-HT trending toward significance (P = 0.09). After T3-SCI, the MCA had more collagen I (42%), collagen III (24%), transforming growth factor β (47%) and angiotensin II receptor type 2 (132%), 27% less elastin as well as concurrent increased wall thickness and reduced lumen diameter (all P < 0.05). Sympathetic innervation (tyrosine hydroxylase-positive axon density) and endothelium-dependent dilatation (carbachol) of the MCA were not different between groups. This study demonstrates profibrosis and hypertrophic inward remodelling within the largest cerebral artery after high-thoracic SCI, leading to increased stiffness and possibly impaired reactivity. These deleterious adaptations would substantially undermine the capacity for regulation of cerebral blood flow and probably underlie several cerebrovascular clinical conditions in the SCI population.

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“…Dorrance et al summarize the studies on obesity and address the obesity paradox (70), that is while obesity increases the stroke risk, the outcomes are better in obese patients. On the other hand in experimental models, ischemic injury and outcomes are worse in obesity.…”

Section: Consequences and Conclusionmentioning

confidence: 99%

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

Coucha

Abdelsaid

Ward

et al. 2018

Comprehensive Physiology

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Metabolic diseases including obesity, insulin resistance, and diabetes have profound effects on cerebral circulation. These diseases not only affect the architecture of cerebral blood arteries causing adverse remodeling, pathological neovascularization, and vasoregression but also alter the physiology of blood vessels resulting in compromised myogenic reactivity, neurovascular uncoupling, and endothelial dysfunction. Coupled with the disruption of blood brain barrier (BBB) integrity, changes in blood flow and microbleeds into the brain rapidly occur. This overview is organized into sections describing cerebrovascular architecture, physiology, and BBB in these diseases. In each section, we review these properties starting with larger arteries moving into smaller vessels. Where information is available, we review in the order of obesity, insulin resistance, and diabetes. We also tried to include information on biological variables such as the sex of the animal models noted since most of the information summarized was obtained using male animals. © 2018 American Physiological Society. Compr Physiol 8:773-799, 2018.

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The Effects of Obesity on the Cerebral Vasculature

Cited by 80 publications

References 129 publications

Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction

Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction

Rigid and remodelled: cerebrovascular structure and function after experimental high‐thoracic spinal cord transection

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

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