title: Heme oxygenase 1 is differentially involved in blood flow-dependent arterial remodeling: role of inflammation, oxidative stress, and nitric oxide.
abstract: 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.
authors.affiliation: Department of Integrated Neurovascular Biology, UMR CNRS 6214, INSERM U771, Faculté de Médecine, 49045 Angers, France.
authors.forename: Mohamed Lamine
authors.initials: ML
authors.lastname: Freidja
authors.forename: Bertrand
authors.initials: B
authors.lastname: Toutain
authors.forename: Antoine
authors.initials: A
authors.lastname: Caillon
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret
authors.forename: Diane
authors.initials: D
authors.lastname: Lambert
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000098:Acetophenones; D008665:Metalloporphyrins; D011524:Protoporphyrins; D009569:Nitric Oxide; C056165:acetovanillone; C032628:tin protoporphyrin IX; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1