title: Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation.
abstract: To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Basic and Translational Stroke Research, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and 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; and.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: Department of Health Policy, Management and Leadership, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Basic and Translational Stroke Research, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Frisbee
authors.affiliation: Division of Exercise Physiology, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and.
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; Center for Basic and Translational Stroke Research, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Chantler
authors.affiliation: Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Tabone
authors.affiliation: Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and.
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: d'Audiffret
authors.affiliation: Department of Family Medicine, West Virginia University Health Sciences Center, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia; and.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Shrader
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; and.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Goodwill
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; and.
authors.forename: Phoebe A
authors.initials: PA
authors.lastname: Stapleton
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; and.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Brooks
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; and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brock
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
mesh_terms: D000818:Animals; D001160:Arterioles / Q000503:physiopathology; D005632:Fructose / Q000494:pharmacology; D006977:Hypertension, Renal / Q000503:physiopathology; D008833:Microcirculation; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D010477:Perfusion; D016491:Peripheral Vascular Diseases / Q000503:physiopathology*; D051381:Rats; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018570:Risk Assessment; D012982:Sodium, Dietary / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism
chemical_list: D012982:Sodium, Dietary; D005632:Fructose; D009569:Nitric Oxide; D013928:Thromboxane A2
keywords: blood flow regulation; microvascular dysfunction; peripheral vascular disease; rodent models of cardiovascular disease risk; system biology of microcirculation