Vascular dysfunction produced by hyperhomocysteinemia is more severe in the presence of low folate

Earlier we reported that dietary folate depletion causes hyperhomocysteinemia (HHcy) and arterial dysfunction in rats (Symons JD, Mullick AE, Ensunsa JL, Ma AA, and Rutledge JC. Arterioscler Thromb Vasc Biol 22: 772-780, 2002). Both HHcy and low folate (LF) are risk factors for cardiovascular disease. Therefore, the dysfunction we observed could have resulted from HHcy, LF, and/or their combination (HHcy + LF). We tested the hypothesis that HHcy-induced vascular dysfunction is more severe in the presence of LF. Four groups of rats consumed diets for ~10 wk that produced plasma homocysteine ((mu)M) and liver folate ((mu)g folate/g liver) concentrations, respectively, of 7 plus or minus 1 and 15 plus or minus 1 (Control; Con; n = 16), 17 plus or minus 2 and 15 plus or minus 2 (HHcy; n = 17), 10 plus or minus 1 and 8 plus or minus 1 (LF; n = 14), and 21 plus or minus 2 and 8 plus or minus 1 (HHcy + LF; n = 18). We observed that maximal ACh-evoked vasorelaxation was greatest in aortas and mesenteric arteries from Con rats vs. all groups. While the extent of dysfunction was similar between LF and HHcy animals, it was less severe compared with arteries from HHcy + LF rats. Maximal ACh-evoked vasorelaxation in coronary arteries was not different between Con and LF rats, but both were greater than HHcy + LF animals. In segments of aortas, 1) ACh-evoked vasorelaxation was similar among groups after incubation with the nonenzymatic intracellular O scavenger Tiron, 2) vascular O estimated using dihydroethidium staining was greatest in HHcy + LF vs. all groups, and 3) tension development in response to nitric oxide (NO) synthase inhibition was greatest in Con vs. all other groups. We conclude that HHcy + LF evokes greater dysfunction than either HHcy alone (aortas, mesentery) or LF alone (aortas, mesentery, coronary), likely by producing more O within the vasculature and thereby reducing NO bioavailability. [PUBLICATION ABSTRACT]