Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats

Am J Physiol Heart Circ Physiol. 2015 Dec 1;309(11):H1846-59. doi: 10.1152/ajpheart.00691.2015. Epub 2015 Oct 16.

Abstract

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS.

Keywords: arterial stiffness; cerebrovascular remodeling; metabolic syndrome; reactive oxygen species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Antihypertensive Agents / pharmacology
  • Antioxidants / pharmacology
  • Biomechanical Phenomena
  • Cerebrovascular Circulation* / drug effects
  • Cerebrovascular Disorders / blood
  • Cerebrovascular Disorders / physiopathology*
  • Cerebrovascular Disorders / prevention & control
  • Disease Models, Animal
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Inflammation Mediators / blood
  • Male
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / drug therapy
  • Metabolic Syndrome / physiopathology*
  • Middle Cerebral Artery / drug effects
  • Middle Cerebral Artery / metabolism
  • Middle Cerebral Artery / physiopathology*
  • Nitric Oxide / metabolism
  • Obesity / blood
  • Obesity / drug therapy
  • Obesity / physiopathology*
  • Oxidative Stress
  • Rats, Zucker
  • Vascular Remodeling
  • Vascular Resistance* / drug effects
  • Vascular Stiffness
  • Vasodilation
  • Vasodilator Agents / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Antihypertensive Agents
  • Antioxidants
  • Inflammation Mediators
  • Vasodilator Agents
  • Nitric Oxide