title: Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats.
abstract: Evolution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-α levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-α blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome.
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia jefrisbee@hsc.wvu.edu.
authors.forename: Jefferson C
authors.initials: JC
authors.lastname: Frisbee
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Goodwill
authors.affiliation: Department of Health Policy, Management and Leadership, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Frisbee
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brock
authors.affiliation: Division of Exercise Physiology, West Virginia University Health Sciences Center, Morgantown, West Virginia; and Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: I Mark
authors.initials: IM
authors.lastname: Olfert
authors.affiliation: Division of Exercise Physiology, West Virginia University Health Sciences Center, Morgantown, West Virginia; and Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Evan R
authors.initials: ER
authors.lastname: DeVallance
authors.affiliation: Division of Exercise Physiology, West Virginia University Health Sciences Center, Morgantown, West Virginia; and Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Chantler
mesh_terms: D000818:Animals; D008297:Male; D055806:Microvessels / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013928:Thromboxane A2
keywords: chronic inflammation; nitric oxide bioavailability; rodent models of obesity; skeletal muscle perfusion; vascular reactivity; vascular remodeling