Heme oxygenase-1 induction restores high-blood-flow-dependent remodeling and endothelial function in mesenteric arteries of old rats

Freidja, Mohamed Lamine; Vessières, Emilie; Clere, Nicolas; Desquiret, Valérie; Guihot, Anne‐Laure; Toutain, Bertrand; Loufrani, Laurent; Jardel, A.; Procaccio, Vincent; Faure, Sébastien; Henrion, Didier

doi:10.1097/hjh.0b013e32833db36e

Cited by 29 publications

(31 citation statements)

References 44 publications

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“…22 They also do not support findings suggesting that overproduction of CO caused by overexpression of HO-1 in vascular smooth muscle cells blunts vasodilatation in response to NO. 23 The present results do not permit further speculation on the reasons for those apparent discrepancies.…”

Section: Et Al Ho-1 Impairs Endothelium-dependent Contractions 931mentioning

confidence: 83%

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Wang

Vanhoutte

2011

Hypertension

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Abstract-Heme oxygenase converts heme to carbon monoxide, biliverdin (subsequently converted to bilirubin), and free iron. Pharmacological induction of heme oxygenase 1 has an antihypertensive effect in the spontaneously hypertensive rat. The present study investigated whether upregulation of heme oxygenase 1 by hemin reduces endothelial dysfunction in this animal. Thirty-six-week-old rats were divided into a hemin treatment (50 mg/kg, IP injection, once) and a control group. Aortas were isolated for the measurement of isometric tension, production of reactive oxygen species, and heme oxygenase activity, as well as gene and protein expressions. Hemin treatment augmented the expression and activity of heme oxygenase 1. This in vivo induction of heme oxygenase 1, but not in vitro incubation with the heme oxygenase products carbon monoxide or bilirubin, led to an improvement of endothelial function in that acetylcholine-induced relaxations were potentiated and acetylcholine-and calcium ionophore-induced contractions were attenuated. Free radical production was suppressed by hemin treatment, judging from the results of 2Ј,7Ј-dichlorodihydrofluoresein diacetate staining, dihydroethidium staining, and lucigenin chemiluminescence, which was explained by the decreased expressions of NADPH oxidase 2 and cyclooxygenase 1. The production of prostacyclin was decreased by heme oxygenase 1 induction, which was explained by a lower expression of cyclooxygenase 1. Contractions to vasoconstrictor concentrations of prostacyclin and its mimetic iloprost were attenuated, suggesting that the responsiveness of thromboxane-prostanoid receptors to prostacyclin was decreased in hemin-treated rats. The suppressed production of free radicals and prostacyclin and the decrease of thromboxane-prostanoid receptors sensitivity concur to explain the impairment of endothelium-dependent contractions caused by heme oxygenase 1 induction by hemin. Key Words: endothelial dysfunction Ⅲ endothelium-dependent contractions Ⅲ heme oxygenase 1 Ⅲ hemin Ⅲ prostacyclin Ⅲ reactive oxygen species Ⅲ spontaneously hypertensive rat Ⅲ thromboxane-prostanoid receptor T he endothelial cell layer contributes to the regulation of vascular tone by releasing vasodilators, in particular NO. 1 However, the endothelium becomes dysfunctional in aging, hypertension, and diabetes mellitus. 2 Endothelial dysfunction is characterized by a decreased production of NO, as well as an increased generation of vasoconstrictors, in particular cyclooxygenase (COX)-derived prostanoids and reactive oxygen species (ROS), termed endothelium-dependent contracting factors (EDCFs). 2 The production of EDCFs is a hallmark of endothelial dysfunction in the spontaneously hypertensive rat (SHR). 3 Indeed, in the endothelium of the SHR aorta, there is an increased expression of COX-1, increased intracellular calcium concentration, and enhanced production of ROS, endoperoxides, and other prostanoids, which underlies the greater occurrence of endotheliumdependent contractions. 3 The increase of end...

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Section: Et Al Ho-1 Impairs Endothelium-dependent Contractions 931mentioning

confidence: 83%

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Wang

Vanhoutte

2011

Hypertension

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“…The artery located between the two ligated vessels was designed as the HF artery. Arteries located at distance of the ligated arteries were used as control [ Fourteen days after surgery, rats were anesthetized [isoflurane (2.5%)], arterial blood pressure was measured in the carotid artery (13), and blood flow was measured in NF and HF mesenteric arteries using a Transonic flow probe (18). The mesentery was then quickly removed and placed in ice-cold physiological salt solution of the following composition (in mM): 130 NaCl, 15 NaHCO3, 3.7 KCl, 1.2 KH 2PO4, 1.2 MgSO4, 11 glucose, 1.6 CaCl2, and 5 HEPES (pH 7.4, PO 2: 160 mmHg, PCO2: 37 mmHg).…”

Section: Methodsmentioning

confidence: 99%

“…MMPs induce then a partial dissociation of the extracellular matrix (ECM). In the last step, vasodilator agents, such as NO produced by eNOS (14), PGI2 produced by cyclooxygenase (COX)-2 (3), and/or carbon monoxide (CO) produced by heme oxygenase (HO)-1 (17,18), increase arterial diameter until the normalization of wall shear stress (44). In parallel, activation of the ANG II type 1 receptor (AT1R) and of MAPK ERK1/2 allow a compensatory hypertrophy aiming at normalization of wall strain induced by the diameter expansion (11).…”

mentioning

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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“…These changes may contribute to chronically elevated levels of retrograde shear stress with older age,24, 25 and may also impact upon the ability of the vasculature to respond to changes in retrograde shear. Interestingly, previous studies in animals reported distinct adaptations to shear stress between young and older individuals 26, 27, 28, 29. However, no previous study has explored whether prolonged exposure to elevated retrograde shear leads to distinct adaptations in brachial artery vasomotor function between healthy young and older humans.…”

Section: Introductionmentioning

confidence: 98%

Impact of 2‐Weeks Continuous Increase in Retrograde Shear Stress on Brachial Artery Vasomotor Function in Young and Older Men

Thijssen

Schreuder²,

Newcomer

et al. 2015

JAHA

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BackgroundAlthough acute elevation in retrograde shear rate (SR) impairs endothelial function, no previous study has explored the effect of prolonged elevation of retrograde SR on conduit artery vascular function. We examined the effect of 2‐weeks elevation of retrograde SR on brachial artery endothelial function in young and in older men.Methods and ResultsThirteen healthy young (23±2 years) and 13 older men (61±5 years) were instructed to continuously wear a compression sleeve around the right forearm to chronically (2 weeks) elevate brachial artery retrograde SR in 1 arm. We assessed SR, diameter, and flow‐mediated dilation in both the sleeve and contralateral control arms at baseline and after 30 minutes and 2 weeks of continuous sleeve application. The sleeve intervention increased retrograde SR after 30 minutes and 2 weeks in both young and older men (P=0.03 and 0.001, respectively). In young men, brachial artery flow‐mediated dilation % was lower after 30 minutes and 2 weeks (P=0.004), while resting artery diameter was reduced after 2 weeks (P=0.005). The contralateral arm showed no change in retrograde SR or flow‐mediated dilation % (P=0.32 and 0.26, respectively), but a decrease in diameter (P=0.035). In older men, flow‐mediated dilation % and diameter did not change in either arm (all P>0.05).ConclusionsThirty‐minute elevation in retrograde SR in young men caused impaired endothelial function, while 2‐week exposure to elevated levels of retrograde SR was associated with a comparable decrease in endothelial function. Interestingly, these vascular changes were not present in older men, suggesting age‐related vascular changes to elevation in retrograde SR.

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Heme oxygenase-1 induction restores high-blood-flow-dependent remodeling and endothelial function in mesenteric arteries of old rats

Abstract: This opens new perspectives in the treatment of ischemic diseases in aging.

Cited by 29 publications

References 44 publications

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

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

Impact of 2‐Weeks Continuous Increase in Retrograde Shear Stress on Brachial Artery Vasomotor Function in Young and Older Men

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