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(Hypertension. 2004;44:327.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Moderate Hyperhomocysteinemia Decreases Endothelial-Dependent Vasorelaxation in Pregnant But Not Nonpregnant Mice

Robert W. Powers; Robin E. Gandley; David L. Lykins; James M. Roberts

From the Magee-Women’s Research Institute and Department of Obstetrics and Gynecology and Reproductive Sciences (R.W.P., R.E.G., D.L.L., J.M.R.), and Department of Environmental and Occupational Health (R.E.G.), University of Pittsburgh School of Medicine, Pa.

Reprint requests to Robert W. Powers, PhD, Magee-Women’s Research Institute, 204 Craft Ave, Room 620, Pittsburgh, PA 15213. E-mail rsirwp{at}mwri.magee.edu

Increased homocysteine is associated with the pregnancy complication preeclampsia and with later-life cardiovascular disease. Although elevated homocysteine persists after pregnancy, the vascular changes of preeclampsia abate with delivery, and cardiovascular disease occurs decades later. This suggests the vasculature during pregnancy may manifest increased sensitivity to homocysteine. We used the cystathionine-ß synthase (CBS)–deficient transgenic mouse to investigate whether hyperhomocysteinemia would differentially affect vascular function in nonpregnant and pregnant animals. Mesenteric arteries from nonpregnant and midpregnant (14 to 16 days) wild-type, heterozygous, and homozygous CBS-deficient transgenic mice were investigated for their response to vasoconstriction, endothelial-dependent, and endothelial-independent relaxation using an isometric wire myograph system. Endothelial-dependent vasodilation was similar in arteries from nonpregnant heterozygous and wild-type mice. In contrast, endothelial-dependent relaxation was reduced significantly in arteries from pregnant heterozygous animals compared with wild-type mice. Inhibition of NO synthesis blunted relaxation in arteries from pregnant wild-type but not pregnant heterozygous mice. Endothelial-dependent relaxation was restored by in vitro pretreatment with the tetrahydrobiopterin precursor sepiapterin. These data indicate that in pregnant mice, endothelial-dependent vasodilation is more sensitive to the effect of increased homocysteine than arteries from nonpregnant mice. This effect appears to result from a loss in NO-mediated relaxation that may be mediated by the oxidative inactivation of the NO synthase cofactor tetrahydrobiopterin.

Key Words: endothelium • nitric oxide • pregnancy

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