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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Hyperhomocysteinemia increases arterial permeability and stiffness in mice

¹Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, University of California, Davis, California; ²University of Iowa College of Medicine and Cardiovascular Center and Veterans Affairs Medical Center, Iowa City, Iowa; and ³College of Health, University of Utah, Salt Lake City, Utah

Submitted 17 May 2006 ; accepted in final form 20 June 2006

We have reported that hyperhomocysteinemia (HHcy) evoked by folate depletion increases arterial permeability and stiffness in rats and that low folate without HHcy increases arterial permeability in mice. In this study, we hypothesized that HHcy independently increases arterial permeability and stiffness in mice. C57BL/6J mice that received rodent chow and water [control (Con), n = 12] or water supplemented with 0.5% L-methionine (HHcy, n = 12) for 18 ± 3 wk had plasma homocysteine concentrations of 8 ± 1 and 41 ± 1 µM, respectively (P < 0.05), and similar liver folate (12 ± 2 µg folate/g liver). Carotid arterial permeability, assessed as dextran accumulation using quantitative fluorescence microscopy, was greater in HHcy (3.95 ± 0.4 ng·min^–1·cm^–2) versus Con (2.87 ± 0.41 ng·min^–1·cm^–2) mice (P < 0.05). Stress versus strain curves generated using an elastigraph indicated that 1) maximal stress (N/mm²), 2) physiological stiffness (low-strain Young's modulus, mN/mm), and 3) maximal stiffness (high-strain Young's modulus, N/mm) were higher (P < 0.05) in aortas from HHcy versus Con mice. Thus, chronic HHcy increases arterial permeability and stiffness. Carotid arterial permeability also was assessed in age-matched C57BL/6J mice before and after incubation with 1) xanthine (0.4 mg/ml)/xanthine oxidase (0.2 mg/ml; X/XO) to generate superoxide anion (O₂^–) or 50 µM DL-homocysteine in the presence of 2) vehicle, 3) 300 µM diethylamine-NONOate (DEANO; a nitric oxide donor), or 4) 10^–3 M 4,5-dihydroxy-1,3-benzene disulfonic acid (tiron; a nonenzymatic intracellular O₂^– scavenger). Compared with preincubation values, X/XO and DL-homocysteine increased (P < 0.05) permeability by 66 ± 11% and 123 ± 8%, respectively. DL-Homocysteine-induced increases in dextran accumulation were blunted (P < 0.05) by simultaneous incubation with DEANO or tiron. Thus, acute HHcy increases arterial permeability by generating O₂^– to an extent whereby nitric oxide bioavailability is reduced.

cardiovascular risk; methionine; homocysteine; vascular mechanics

This article has been cited by other articles:

				S. Dayal and S. R. Lentz Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes Arterioscler. Thromb. Vasc. Biol., September 1, 2008; 28(9): 1596 - 1605. [Abstract] [Full Text] [PDF]