Published online before print March 7, 2002, doi: 10.1161/01.ATV.0000014588.71807.0A
© 2002 American Heart Association, Inc.
Vascular Biology |
Hyperhomocysteinemia Evoked by Folate Depletion
Effects on Coronary and Carotid Arterial Function
From the College of Health (J.D.S.), University of Utah, Salt Lake City, Utah; Division of Endocrinology (A.E.M., J.C.R.), Clinical Nutrition, and Vascular Medicine; and Department of Nutrition (J.L.E.) and Division of Cardiovascular Medicine (A.A.M.), University of California, Davis, Calif.
Correspondence to J. David Symons, PhD, University of Utah, College of Health, 250 S 1850 E Room 241, Salt Lake City, UT 84112. E-mail j.david.symons{at}hsc.utah.edu
High circulating concentrations of homocysteine (ie, hyperhomocysteinemia [Hhcy]) impair the vascular function of peripheral conduit arteries and arterioles perfusing splanchnic and skeletal muscle regions. The effects of HHcy on coronary resistance vessel function and other indexes of vascular function, ie, arterial permeability and stiffening, are unclear. We tested the hypotheses that HHcy impairs coronary resistance vessel reactivity; increases carotid arterial permeability; and initiates arterial stiffening. Male rats that consumed folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to 5 weeks had total plasma homocysteine concentrations of 7±2 or 58±4 µmol/L, respectively. Maximal acetylcholine-evoked relaxation (
40% vs 60%) and tension development from baseline in response to nitric oxide synthase inhibition (20% vs 40%) were lower (both P<0.05) in coronary resistance vessels (120 µm, internal diameter) isolated from HHcy versus CON animals, respectively, whereas sodium nitroprusside-evoked relaxation and contractile responses to serotonin and potassium chloride were similar between groups. Permeability to 4400 MW and 65 000 MW fluorescently labeled (TRITC) dextran reference macromolecules (quantitative fluorescence microscopy) was 44% and 24% greater (P<0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less (32% vs 42%, P<0.05) in carotid arterial segments from HHcy versus CON animals, respectively. Finally, estimates of oxidative (copper-zinc+manganese superoxide dismutase activity) and glycoxidative (pentosidine) stress were elevated (P<0.05) in arterial tissue from HHcy versus CON rats. These findings suggest that moderately severe HHcy evoked by folate-depletion impairs endothelium-dependent relaxation of coronary resistance vessels, increases carotid arterial permeability, and initiates arterial stiffening. HHcy may produce these effects by a mechanism associated with increased oxidative and glycoxidative stress.
Key Words: coronary resistance artery • rat • arterial stiffness • arterial permeability • vascular reactivity
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