The AGE-Breaker ALT-711 Restores High Blood Flow–Dependent Remodeling in Mesenteric Resistance Arteries in a Rat Model of Type 2 Diabetes

Freidja, Mohamed Lamine; Tarhouni, Kahena; Toutain, Bertrand; Fassot, Céline; Loufrani, Laurent; Henrion, Didier

doi:10.2337/db11-0750

Cited by 43 publications

(33 citation statements)

References 47 publications

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“…It contributes to the prevention of further tissue injury (eg, in limb or myocardial ischemia). FMR has been shown to be reduced by hypertension,58, 59 diabetes mellitus,60, 61 and aging 11, 62. More important and rather unexpectedly, we previously reported that FMR depends on the presence of ERα15, 63 and could contribute to the better resistance to ischemia/necrosis of female compared with male mice.…”

Section: Discussionmentioning

confidence: 76%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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BackgroundAlthough estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization.Methods and ResultsUsing mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling.ConclusionsAltogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

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Section: Discussionmentioning

confidence: 76%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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“…Thus, a change in the NO pathway is not likely to explain the absence of diameter expansion. Consequently, we investigated oxidative stress, which is involved in flow-mediated remodeling (2,8,16,19) and arterial contractility (10). Our data showed a larger contractile response to phenylephrine in HF arteries of 12-mo-old male rats.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic increases in blood flow occur in physiological conditions such as growth, chronic exercise, or pregnancy as well as in ischemic disorders, where they contribute to collateral arteries growth (7, 36). Flowmediated outward remodeling of resistance arteries involves a transient inflammatory response (1) and oxidative stress (2) that favors the formation of peroxinitrite, which then activates metalloproteinases and extracellular matrix digestion (2,8,14,16,19). The final step, leading to diameter enlargement, requires a dilator stimulus (17).…”

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confidence: 99%

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

Tarhouni

Freidja

Guihot³

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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tance arteries, a chronic increase in blood flow induces hypertrophic outward remodeling. This flow-mediated remodeling (FMR) is absent in male rats aged 10 mo and more. As FMR depends on estrogens in 3-mo-old female rats, we hypothesized that it might be preserved in 12-mo-old female rats. Blood flow was increased in vivo in mesenteric resistance arteries after ligation of the side arteries in 3-and 12-mo-old male and female rats. After 2 wk, high-flow (HF) and normal-flow (NF) arteries were isolated for in vitro analysis. Arterial diameter and cross-sectional area increased in HF arteries compared with NF arteries in 3-mo-old male and female rats. In 12-mo-old rats, diameter increased only in female rats. Endothelial nitric oxide synthase expression and endothelium-mediated relaxation were higher in HF arteries than in NF arteries in all groups. ERK1/2 phosphorylation, NADPH oxidase subunit expression levels, and arterial contractility to KCl and to phenylephrine were greater in HF vessels than in NF vessels in 12-mo-old male rats only. Ovariectomy in 12-mo-old female rats induced a similar pattern with an increased contractility without diameter increase in HF arteries. Treatment of 12-mo-old male rats and ovariectomized female rats with hydralazine, the antioxidant tempol, or the angiotensin II type 1 receptor blocker candesartan restored HF remodeling and normalized arterial contractility in HF vessels. Thus, we found that FMR of resistance arteries remains efficient in 12-mo-old female rats compared with age-matched male rats. A balance between estrogens and vascular contractility might preserve FMR in mature female rats. microcirculation; remodeling; blood flow; shear stress; sex; aging; estrogen RESISTANCE ARTERIES control local blood flow to organs. They are able to adapt in response to changes in hemodynamic conditions, even in the adult. A chronic increase in blood flow (shear stress) in these vessels induces outward hypertrophic remodeling associated with increased endothelium [nitric oxide (NO)]-dependent dilation, as shown in male (2,5, 33) and female rats (37). Chronic increases in blood flow occur in physiological conditions such as growth, chronic exercise, or pregnancy as well as in ischemic disorders, where they contribute to collateral arteries growth (7, 36). Flowmediated outward remodeling of resistance arteries involves a transient inflammatory response (1) and oxidative stress (2) that favors the formation of peroxinitrite, which then activates metalloproteinases and extracellular matrix digestion (2,8,14,16,19). The final step, leading to diameter enlargement, requires a dilator stimulus (17). Flow-mediated outward remodeling is also associated with a compensatory increase in wall mass (11, 32) due to ANG II type 1 receptor activation of ERK1/2 (11).As shown in male rats, flow-mediated remodeling of mesenteric resistance arteries does not occur in male rats aged 12 mo (40) or 24 mo (15). Although no diameter enlargement occurred in arteries after increasing blood flow, endotheliummedia...

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“…The mRNA levels for the following proteins were determined as previously described 26 using real-time polymerase chain reaction: MCP1, CD68, CD11B, COX1, COX2, gp91, p22, p47, metaloproteinases (MMP)2, TIMP1, eNOS, CAV-1, HIF1α, VEGFA, and TGFβ1 on HF and NF mesenteric arteries from OVX rats either treated with E2 or left untreated.…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

Tarhouni

Guihot

Freidja

et al. 2013

ATVB

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Objective-Flow-(shear stress-)mediated outward remodeling of resistance arteries is involved in collateral growth during postischemic revascularization. As this remodeling is especially important during pregnancy, we hypothesized that estrogens may be involved. A surgical model eliciting a local increase in blood flow in 1 mesenteric resistance artery was used in 3-month-old ovariectomized female rats either treated with 17-β-estradiol (E2) or left untreated. Methods and Results-After 14 days, arterial diameter was greater in high-flow arteries than in normal-flow vessels. An ovariectomy suppressed high-flow remodeling, while E2 restored it. High-flow remodeling was absent in mice lacking the estrogen receptor α but not estrogen receptor β. The kinetics of inflammatory marker expression, macrophage infiltration, oxidative stress, and metaloproteinases expression were not altered by the absence of E2 after 2 and 4 days, that is, during remodeling. Nevertheless, E2 was required for the increase in endothelial nitric oxide synthase expression and activation at day 4 when diameter expansion occurs. Finally, the impact of E2 on the endothelium appeared crucial for high-flow remodeling, as this E2 action was abrogated in mice lacking endothelial NOS, as well as in Tie2-Cre(+) ERα f/f mice. Conclusion-We

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The AGE-Breaker ALT-711 Restores High Blood Flow–Dependent Remodeling in Mesenteric Resistance Arteries in a Rat Model of Type 2 Diabetes

Cited by 43 publications

References 47 publications

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

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