Influence of folate on arterial permeability and stiffness in the absence or presence of hyperhomocysteinemia

Objective - Elevated plasma total homocysteine (tHcy) is associated with risk for cardiovascular disease. A common cause of mild hyperhomocysteinemia (HHcy) is folate deficiency. We sought to determine whether folate deficiency per se increases arterial permeability (quantitative fluorescence microscopy) and stiffness (vessel elastigraph), and whether the effects of folate deficiency are more severe in the presence of mild HHcy. Methods and Results - Heterozygous cystathionine β-synthase (CBS)-deficient mice (CBS ^+/-) and their wild-type littermates (CBS^+/+) were fed chow containing either standard (Con) or relatively low amounts of folate (LF) for 18±3 weeks. Liver folate (μg folate/g liver) and tHcy (μM), respectively, were 12±1 and 8±1 in CBS^+/+ Con mice (n=12), and 8±1 and 8±1 in CBS^+/+ LF animals (n=5). Carotid arterial permeability was ≈38% greater (P<0.05) in CBS ^+/+ LF versus Con mice, but vascular stiffening was unaltered. Liver folate and tHcy, respectively, were 13±1 and 11±1 in CBS ^+/- Con mice (n=16), and 8±1 and 16±3 in CBS ^+/- LF animals (n=6). Carotid arterial dextran accumulation was ≈31% greater, and maximal strain in aortae was ≈20% lower (both P<0.05) in CBS^+/- LF versus Con mice. Conclusion - Taken together, low folate (P<0.05) combined with mild HHcy (P<0.05) in CBS^+/- mice produced more arterial dysfunction compared with low folate alone (ie, CBS ^+/+ mice). These findings may be particularly relevant to elderly individuals because tHcy and deficiencies of folate metabolism increase with age.