Heme oxygenase 1 is differentially involved in blood flow-dependent arterial remodeling: role of inflammation, oxidative stress, and nitric oxide

Heme oxygenase 1 is induced by hemodynamic forces in vascular smooth muscle and endothelial cells. We investigated the involvement of heme oxygenase 1 in flow (shear stress)-dependent remodeling. Two or 14 days after ligation of mesenteric resistance arteries, vessels were isolated. In rats, at 14 days, diameter increased by 23% in high-flow arteries and decreased by 22% in low-flow arteries compared with normal flow vessels. Heme oxygenase activity inhibition using Tin-protoporphyrin abolished diameter enlargement in high-flow arteries and accentuated arterial narrowing in low-flow arteries (32% diameter decrease versus 22% in control). Two days after ligation, heme oxygenase 1 expression increased in high-flow and low-flow vessels, in association with a reduced mitochondrial aconitase activity (marker of oxidative stress) in high-flow arteries only. Inhibition of macrophage infiltration (clodronate) decreased heme oxygenase 1 induction in low-flow but not in high-flow arteries. Similarly, inhibition of NADPH oxidase activity (apocynin) decreased heme oxygenase 1 induction in low-flow but not high-flow arteries. However, dihydroethidium staining was higher in high-flow and low-flow compared with normal flow arteries. In arteries cannulated in an arteriograph, heme oxygenase 1 mRNA increased in a flow-dependent manner and was abolished by N(G)-nitro-l-arginine methyl ester, catalase, or mitochondrial electron transport chain inhibition. Furthermore, heme oxygenase 1 induction using cobalt-protoporphyrin restored altered high-flow remodeling in endothelial NO synthase knockout mice. Thus, in high-flow remodeling, heme oxygenase 1 induction depends on shear stress-generated NO and mitochondria-derived hydrogen peroxide. In low-flow remodeling, heme oxygenase 1 induction requires macrophage infiltration and is mediated by NADPH oxidase-derived superoxide

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

BACKGROUND: Aging is associated with reduced structural and functional adaptation to chronic changes in blood flow (shear stress) in small arteries. As heme oxygenase-1 (HO-1) is induced by hemodynamic forces in vascular smooth muscle and endothelial cells, we hypothesized that it might improve flow-dependent remodeling in aging. METHOD: First-order mesenteric arteries from 3 and 16-month-old rats were exposed to high, low, or normal flow by alternate ligation in vivo. Rats were treated with the HO-1 inducer, cobalt protoporphyrin (CoPP, 5 mg/kg) or vehicle. 14 days later, local blood flow was measured in vivo, and arteries were studied in vitro. RESULTS: Despite an equivalent change in blood flow, diameter enlargement in the high-flow arteries was blunted in old compared to young rats and was associated with decreased endothelium-dependent relaxation to acetylcholine. In old rats, HO-1 induction with CoPP restored outward remodeling, via a paradoxical reactive oxygen species-dependent mechanism, and was associated with a Mn-superoxide dismutase (SOD) overexpression, as well as a significant reduction of mitochondrial aconitase activity, used as a biomarker for oxidative stress. The heme oxygenase activity inhibitor, Sn-protoporphyrin, and the SOD-mimetic, TEMPOL, prevented the effect of CoPP on remodeling and oxidative status in old rats. Furthermore, HO-1 induction improved endothelial function, in association with increased endothelial nitric oxide synthase protein expression and phosphorylation (Ser-1177). In low-flow arteries, inward remodeling was unaffected by aging or by CoPP. Thus, in old rats, CoPP-induced up-regulation of HO-1 restored high-flow-dependent remodeling (diameter enlargement) and improved endothelial function in mesenteric arteries. CONCLUSION: This opens new perspectives in the treatment of ischemic diseases in aging

Impact of retrograde shear rate on brachial and superficial femoral artery flow-mediated dilation in older subjects

An inverse, dose-dependent relationship between retrograde shear rate and brachial artery endothelial function exists in young subjects. This relationship has not been investigated in older adults, who have been related to lower endothelial function, higher resting retrograde shear rate and higher risk of cardiovascular disease. Aim To investigate the impact of a step-wise increase in retrograde shear stress on flow-mediated dilation in older males in the upper and lower limbs. Methods Fifteen older (68±9 years) men reported to the laboratory 3 times. We examined brachial artery flow-mediated dilation before and after 30-minutes exposure to cuff inflation around the forearm at 0, 30 and 60 mmHg, to manipulate retrograde shear rate. Subsequently, the 30-minute intervention was repeated in the superficial femoral artery. Order of testing (vessel and intervention) was randomised. Results Increases in cuff pressure resulted in dose-dependent increases in retrograde shear in both the brachial and superficial femoral artery in older subjects. In both the brachial and the superficial femoral artery, no change in endothelial function in response to increased retrograde shear was observed in older males (‘time’ P=0.274, ‘cuff*time P=0.791’, ‘cuff*artery*time P=0.774’). Conclusion In contrast with young subjects, we found that acute elevation in retrograde shear rate does not impair endothelial function in older humans. This may suggest that subjects with a priori endothelial dysfunction are less responsive or requires a larger shear rate stimulus to alter endothelial function

Remodelage des artères mésentériques de résistance en réponse au changement chronique de débit sanguin (rôle de l'hème oxygénase-1)

L'incidence de l'hypertension, les maladies coronariennes, les maladies ischémiques et l'insuffisance cardiaque augmente très fortement avec le vieillissement. Cela pourrait s'expliquer, au moins en partie, par l'altération avec l'âge de la capacité des artères de répondre correctement à un changement chronique de débit. Nous avons émis l'hypothèse que l'enzyme Hème Oxygénase-1 (HO-1) peut être induite dans les artères de résistance soumises à une augmentation chronique de flux sanguin, in vivo, et nous avons cherché à comprendre le rôle de HO-1 au cours du remodelage flux-dépendant. Nos résultats nous ont permis d'étendre les observations de notre laboratoire relatives au rôle important des stress oxydatif et nitrosatif dans le remodelage, pour ajouter un nouveau chaînon à la cascade des évènements qui est l'induction de HO-1.Etant impliquée aussi bien dans le remodelage HF (High Flow) que celui de LF (Low Flow), l'induction de HO-1 représente un avantage double dans les maladies ischémiques, i) en retradant le rétrécissement artériel où la circulation sanguine est affaiblie et ii) en favorisant la réponse expansive des artères latérales pour une irrigation compensatoire efficace. Aussi, nous avons démontré que l'induction de HO-1 permet de rétablir la capacité des petites artères de résistance des rats âgés de se remodeler en réponse à une augmentation chronique du débit sanguin. De manière très intéressante, cette adaptation structurale était accompagnée d'une amélioration significative de la fonction endothéliale des artères étudiées. Ainsi, la surexpression de HO-1 représente un intérêt préventif et/ou thérapeutique lors du processus de vieillissement artériel.The incidence oh hypertension, coronary diseases, ischemic diseases and heart failure increases dramatically in aging. This could be explained, at least in part, by the alteration of arteries ability to respond adequately to chronic changes in blood flow.We hypothesized that heme oxygenase-1 (HO-1) can be induced in resitance arteries submitted to a chronic increasd in blood flow, in vivo, and we aimed to understand the role of HO-1 in flow -dependant remodeling.Our results have extended previous observations of our laboratory on the role of oxidative and nitrosative stress in vascular remodeling to add a new link in flow-dependant remodeling pathway, which is the induction of HO-1.As it is involved in both HF and LF remodeling, HO-1 induction offers a double avantage in the case of ischemic diseases by i) delaying arterial narrowing in arteries where blood flow is decreased, and, ii) promoting the expansive response of collateral vessels, thus providing more efficient compensatory irrigation of downstream tissues. Both of these activities are required to prevent irreversible ischemia-induced injury. In addition, we demonstrated that upregulation of HO-1 restored the impaired capacity of mesenteric arteries from old rats to remodel in response to a chronic increase in blood flow. Interestingly, this structural adaptation was accompanied by a significant improvement in endothelial function of resistance arteries. Thus, stimulation of HO-1 expression may have preventive and/or therapeutic potential in the aging process of resistance arteries, associated with an altered capacity to adapt in response to chronic changes in local blood flow.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Flow (shear stress)-mediated remodeling of resistance arteries in diabetes.

International audienceShear stress due to blood flow is the most important force stimulating vascular endothelium. Acute stimulation of the endothelium by shear stress induces a vasodilatation mainly due to the release of nitric oxide (NO) among other relaxing agents. After a chronic increase in blood flow (shear stress), the endothelium triggers diameter enlargement, medial hypertrophy and improvement of arterial contractility and endothelium-mediated dilation. Shear stress-mediated outward remodeling requires an initial inflammatory response followed by the production of reactive oxygen species (ROS) and peroxinitrite anions, which activate MMPs and extracellular matrix digestion allowing diameter expansion. This outward remodeling occurs in collateral growth following occlusion of a large artery. In diabetes, an excessive ROS production is associated with the formation of advanced glycation end-products (AGEs) and the glycation of enzymes involved in vascular tone. The balance between inflammation, AGEs and ROS level determines the ability of resistance arteries to develop outward remodeling whereas AGEs and ROS contribute to decrease endothelium-mediated dilation in remodeled vessels. This review explores the interaction between ROS, AGEs and the endothelium in shear stress-mediated outward remodeling of resistance arteries in diabetes. Restoring or maintaining this remodeling is essential for an efficient blood flow in distal organs

The AGE-breaker ALT-711 restores high blood flow-dependent remodeling in mesenteric resistance arteries in a rat model of type 2 diabetes.: AGEs oppose flow-mediated remodeling

International audienceFlow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases, but this is impaired in diabetes. We hypothesized that breaking advanced glycation end product (AGE) cross-links could improve remodeling in mesenteric resistance arteries in Zucker diabetic fatty (ZDF) rats compared with lean Zucker (LZ) rats. Arteries, exposed to high (HF) or normal (NF) blood flow after alternate arterial ligation in vivo, were collected after 2 weeks. In LZ rats, HF artery diameter was larger than for NF vessels, but this was not the case in ZDF rats. Endothelium-mediated dilation in ZDF rats, which was lower than in LZ rats, was further decreased in HF arteries. Treatment of rats with the AGE-breaker 4,5-dimethyl-3-phenacylthiazolium chloride (ALT-711) (3 mg/kg/day; 3 weeks) reversed diabetes-induced impairment of HF-dependent remodeling. ALT-711 also improved endothelium nitric oxide-dependent relaxation in mesenteric resistance arteries. Reactive oxygen species reduction restored relaxation in ZDF rats but not in LZ or ALT-711-treated rats. AGEs were reduced in ALT-711-treated ZDF rats compared with ZDF rats. Metalloproteinase activity, necessary for HF-dependent remodeling, was reduced in ZDF rats compared with LZ rats and restored by ALT-711. Thus, targeting AGE cross-links may provide a therapeutic potential for overcoming microvascular complications in ischemic disorders occurring in diabetes