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Hyperhomocysteinemia evoked by folate depletion: effects on coronary and carotid arterial function
J David Symons1, Adam E Mullick, Jodi L Ensunsa
1College of Health, University of Utah, Salt Lake City, Utah 84112, USA. j.david.symons@hsc.utah.edu
Insights
High homocysteine (Hhcy) impairs coronary vessel function and increases arterial permeability and stiffening. Folate-depleted rats showed reduced relaxation and increased arterial stiffness, suggesting Hhcy
Area of Science:
- Cardiovascular Physiology
- Vascular Biology
- Nutritional Biochemistry
Background:
- High circulating homocysteine (hyperhomocysteinemia, Hhcy) is known to impair vascular function in peripheral arteries.
- The specific effects of Hhcy on coronary resistance vessels, arterial permeability, and arterial stiffening remain unclear.
- Understanding these effects is crucial for comprehending Hhcy's broader cardiovascular impact.
Purpose of the Study:
- To test the hypotheses that Hhcy impairs coronary resistance vessel reactivity.
- To investigate if Hhcy increases carotid arterial permeability.
- To determine if Hhcy initiates arterial stiffening.
Main Methods:
- Male rats were fed either folate-replete (CON) or folate-deplete (HHcy) chow for 4-5 weeks.
- Coronary resistance vessel function was assessed using isolated vessel studies.
- Carotid arterial permeability was measured using fluorescently labeled dextran, and arterial stiffening was evaluated with a vessel elastigraph.
Main Results:
- HHcy rats exhibited impaired endothelium-dependent relaxation and reduced tension development in coronary resistance vessels compared to CON rats.
- Carotid arteries from HHcy rats showed significantly increased permeability to macromolecules.
- Arterial segments from HHcy rats demonstrated reduced maximal strain, indicating increased arterial stiffening.
Conclusions:
- Moderately severe hyperhomocysteinemia, induced by folate depletion, impairs coronary resistance vessel endothelium-dependent relaxation.
- Hhcy increases carotid arterial permeability and initiates arterial stiffening.
- These vascular impairments may be mediated by increased oxidative and glycoxidative stress.
Abstract:
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 micromol/L, respectively. Maximal acetylcholine-evoked relaxation (approximately 40% vs approximately 60%) and tension development from baseline in response to nitric oxide synthase inhibition (approximately 20% vs approximately 40%) were lower (both P<0.05) in coronary resistance vessels (approximately 120 microm, 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 approximately 44% and approximately 24% greater (P<0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less ( approximately 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.