Aldosterone: good guy or bad guy in cerebrovascular disease?

Rigsby, Christine S.; Cannady, William; Dorrance, Anne M.

doi:10.1016/j.tem.2005.09.002

Cited by 22 publications

(18 citation statements)

References 65 publications

(89 reference statements)

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“…Another potential factor is aldosterone. Plasma aldosterone levels are elevated in adult ␤ENaC m/m mice, and mineralocorticoid receptor activation can induce vascular remodeling (16). However, a lack of evidence for vascular remodeling at 6 -8 wk of age does not support a role for elevated aldosterone.…”

Section: Discussionmentioning

confidence: 99%

Pressure-induced constriction is inhibited in a mouse model of reduced βENaC

VanLandingham¹,

Gannon²,

Drummond³

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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VanLandinghamLG, Gannon KP, Drummond HA. Pressureinduced constriction is inhibited in a mouse model of reduced ␤ENaC. Am J Physiol Regul Integr Comp Physiol 297: R723-R728, 2009. First published June 24, 2009 doi:10.1152/ajpregu.00212.2009.-Recent studies suggest certain epithelial Na ϩ channel (ENaC) proteins may be components of mechanosensitive ion channel complexes in vascular smooth muscle cells that contribute to pressure-induced constriction in middle cerebral arteries (MCA). However, the role of a specific ENaC protein, ␤ENaC, in pressure-induced constriction of MCAs has not been determined. The goal of this study was to determine whether pressure-induced constriction in the MCA is altered in a mouse model with reduced levels of ␤ENaC. Using quantitative immunofluorescence, we found whole cell ␤ENaC labeling in cerebral vascular smooth muscle cells (VSMCs) was suppressed 46% in ␤ENaC homozygous mutant (m/m) mice compared with wild-type littermates (ϩ/ϩ). MCAs from ␤ENaC ϩ/ϩ and m/m mice were isolated and placed in a vessel chamber for myographic analysis. Arteries from ␤ENaCϩ/ϩ mice constricted to stepwise increases in perfusion pressure and developed maximal tone of 10 Ϯ 2% at 90 mmHg (n ϭ 5). In contrast, MCAs from ␤ENaC m/m mice developed significantly less tone (4 Ϯ 1% at 90 mmHg, n ϭ 5). Vasoconstrictor responses to KCl (4 -80 mM) were identical between genotypes and responses to phenylephrine (10 Ϫ7 -10 Ϫ4 M) were marginally altered, suggesting that reduced levels of VSMC ␤ENaC specifically inhibit pressure-induced constriction. Our findings indicate ␤ENaC is required for normal pressure-induced constriction in the MCA and provide further support for the hypothesis that ␤ENaC proteins are components of a mechanosensor in VSMCs.epithelial Na ϩ channel; ion channel; degenerin; myogenic constriction; middle cerebral artery VASCULAR SMOOTH MUSCLE CELLS (VSMCs) from most smallresistance arteries have the ability to constrict in response to increases in intraluminal pressure, a response referred to as pressure-induced, or myogenic constriction (3,8,9). Pressureinduced constriction contributes to the autoregulation of cerebral blood flow and may prevent transmission of systemic pressure to microvessels (3,8,9). The response involves transduction of pressure-induced stretch into a cellular event (vasoconstriction). Mechanosensitive ion channels are thought to participate in the initiation of the response. However, the molecules involved in initiating the response have not been fully characterized (3,8,9).Recent studies suggest members of the degenerin (DEG) protein family, which includes epithelial Na ϩ channel (ENaC) and acid-sensing ion channel (ASIC) proteins, are candidates for mechanosensitive ion channels because DEG proteins are linked to mechanotransduction (5,6,14,15). DEG proteins are expressed in mechanosensitive tissues, such as smooth muscle and neuronal tissue in a diverse range of species (nematode, Drosophila, and mammals). Disruption of channel expression alters normal mechanosensory resp...

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Section: Discussionmentioning

confidence: 99%

Pressure-induced constriction is inhibited in a mouse model of reduced βENaC

VanLandingham¹,

Gannon²,

Drummond³

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…31 Because elevated plasma aldosterone is associated with increased stroke risk, 32 it is possible that this mediator may contribute to detrimental GPER-dependent effects in the setting of stroke.…”

Section: March 2014mentioning

confidence: 99%

Sex-Dependent Effects of G Protein–Coupled Estrogen Receptor Activity on Outcome After Ischemic Stroke

Broughton

Brait

Kim

et al. 2014

Stroke

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O ur knowledge of estrogen signaling pathways during cerebral ischemia, including the relative importance of different estrogen receptors and identities of estrogen-regulated gene networks affecting neuronal death, remains incomplete. Until recently, estrogen was thought to elicit its neuroprotective actions solely via activation of the classical nuclear receptors, estrogen receptor(ER)α and ERβ.1,2 However, the discovery of a novel estrogen receptor called G protein-coupled estrogen receptor (GPER, formerly known as GPR30), with high expression in the brain 3,4 and cerebral circulation, 5 presents a third receptor that may influence estrogenmediated outcomes after stroke. Important differences exist between GPER and classical estrogen receptors in that GPER responds to estrogen with rapid cellular signaling, and it is a G protein-coupled receptor localized on the plasma membrane 6 and intracellular membranes such as the endoplasmic reticulum and Golgi apparatus. Similar to classical estrogen receptor signaling, there is evidence for neuroprotection after GPER activation in ovariectomized (OVX) animals subjected to stroke. Chronic pretreatment of OVX rodents with the selective GPER agonist, G-1, reduces brain injury after focal or global ischemia. 8,9Interestingly, we have found that GPER distribution and expression is increased in the brain of male mice, but not of intact female or OVX mice, after transient focal ischemia. 4This sex-dependent regulation of GPER expression after cerebral ischemia could help explain some of the complex effects of estrogen in the brain after stroke and also guide the Background and Purpose-Experimental studies indicate that estrogen typically, but not universally, has a neuroprotective effect in stroke. Ischemic stroke increases membrane-bound G protein-coupled estrogen receptor (GPER) distribution and expression in the brain of male but not female mice. We hypothesized that GPER activation may have a greater neuroprotective effect in males than in females after stroke. Methods-Vehicle (dimethyl sulfoxide), a GPER agonist (G-1, 30 μg/kg), or a GPER antagonist (G-15, 300 μg/kg) were administered alone or in combination to young or aged male mice, or young intact or ovariectomized female mice, 1 hour before or 3 hours after cerebral ischemia-reperfusion. Some mice were treated with a combination of G-1 and the pancaspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-V D -OPh), 1 hour before stroke. We evaluated functional and histological end points of stroke outcome up to 72 hours after ischemia-reperfusion. In addition, apoptosis was examined using cleaved caspase-3 immunohistochemistry. Results-Surprisingly, G-1 worsened functional outcomes and increased infarct volume in males poststroke, in association with an increased expression of cleaved caspase-3 in peri-infarct neurons. These effects were blocked by G-15 or Q-VDOPh. Conversely, G-15 improved functional outcomes and reduced infarct volume after stroke in males, whether given before or after stroke. In contrast to find...

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“…Some reports maintain that occupation of MR is part of a cell survival mechanism. For example, activation of MR prevents kainic acid excitotoxicity and increases the anti-apoptotic gene Bcl2 in the hippocampus (16), whereas in the dentate gyrus aldosterone treatment increases neurogenesis and the survival of newborn neurons (42). By contrast, when given chronically in high doses, mineralocorticoids increase the preference for concentrated salt solutions and induce hypertension (8,43).…”

Section: Mineralocorticoids Hypertension and Brain Damagementioning

confidence: 99%

“…humans (16). The central mechanisms implicated in mineralocorticoid effects comprise the increase of sympathetic outflow and inflammatory cytokines (44), interactions with the vasoactive neuropeptides angiotensin II (AngII), natriuretic peptides, and arginine vasopressin (11,45,46) and deleterious remodeling of the cerebral vasculature with exacerbation of ischemic damage (15).…”

Section: Figurementioning

confidence: 99%

“…Hormonal imbalances are frequent companions of hypertension. For example, adrenal steroids and their receptors could participate in the brain abnormalities of experimental hypertension (13)(14)(15), whereas aldosterone plays a role in 10-15% of patients with essential hypertension (16). The known relation between menopause and high blood pressure indicates that a decline of estrogens starts or impairs pre-existing hypertension (17).…”

Section: Introduction: Hypertension and Brain Damagementioning

confidence: 99%

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Protective effect of estrogens on the brain of rats with essential and endocrine hypertension

Nicola¹,

Pietranera²,

Bellini

et al. 2010

Hormone Molecular Biology and Clinical Investigation

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Estrogen neuroprotection has been shown in pathological conditions damaging the hippocampus, such as trauma, aging, neurodegeneration, excitotoxicity, oxidative stress, hypoglycemia, amyloid-β peptide exposure and ischemia. Hypertensive encephalopathy also targets the hippocampus; therefore, hypertension seems an appropriate circumstance to evaluate steroid neuroprotection. Two experimental models of hypertension, spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats, develop hippocampal abnormalities, which include decreased neurogenesis in the dentate gyrus, astrogliosis, low expression of brain-derived neurotrophic factor (BDNF) and decreased number of neurons in the hilar region, with respect of their normotensive strains Wistar Kyoto (WKY) and Sprague-Dawley rats. After estradiol was given for 2 weeks to SHR and DOCA-treated rats, both hypertensive models normalized their faulty hippocampal parameters. Thus, estradiol treatment positively modulated neurogenesis in the dentate gyrus of the hippocampus, according to bromodeoxyuridine incorporation and doublecortin immunocytochemistry, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus and increased neuronal number in the hilar region of the dentate gyrus. A role of local estrogen biosynthesis is suggested in SHR, because basal aromatase mRNA in the hippocampus and immunoreactive aromatase protein in cell processes of the dentate gyrus were highly expressed in these rats. Estradiol further stimulated aromatase-related parameters in SHR but not in WKY. These observations strongly support that a combination of exogenous estrogens to those locally synthesized might better alleviate hypertensive encephalopathy. These studies broaden estrogen neuroprotective functions to the hippocampus of hypertensive rat models.

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Aldosterone: good guy or bad guy in cerebrovascular disease?

Cited by 22 publications

References 65 publications

Pressure-induced constriction is inhibited in a mouse model of reduced βENaC

Pressure-induced constriction is inhibited in a mouse model of reduced βENaC

Sex-Dependent Effects of G Protein–Coupled Estrogen Receptor Activity on Outcome After Ischemic Stroke

Protective effect of estrogens on the brain of rats with essential and endocrine hypertension

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