Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms

Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22±1 years) and 11 older (O: 71±3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVC_max) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM N^G-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVC_max: O=82±3 vs Y=96±1, P=0.002) and NO-dependent vasodilatation (%CVC_max: O=26±6% vs Y=49±5, P=0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVC_max=91±2, P=0.03) and NO-dependent (%CVC_max=43±9%, P=0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVC_max: O=31±8 vs Y=44±5, P=0.001) and NO-dependent (%CVC_max: O=9±2 vs Y=21±2, P=0.003) vasodilatation. Folic acid increased CVC (%CVC_max=47±5%, P=0.001) and NO-dependent vasodilatation (20±3%, P=0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.