Folic Acid Supplementation Improves Microvascular Function in Older Adults Through Nitric Oxide-Dependent Mechanisms

Clin Sci (Lond). 2015 Jul;129(2):159-67. doi: 10.1042/CS20140821.

Abstract

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 (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 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 (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Cutaneous
  • Administration, Oral
  • Age Factors
  • Aged
  • Blood Flow Velocity
  • Body Temperature
  • Cross-Over Studies
  • Dietary Supplements*
  • Double-Blind Method
  • Enzyme Inhibitors / pharmacology
  • Female
  • Folic Acid / administration & dosage*
  • Folic Acid / analogs & derivatives
  • Humans
  • Hypothermia, Induced
  • Male
  • Microcirculation / drug effects*
  • Microdialysis
  • Microvessels / drug effects*
  • Microvessels / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Pennsylvania
  • Regional Blood Flow
  • Skin / blood supply*
  • Vasodilation / drug effects*
  • Vasodilator Agents / administration & dosage*
  • Young Adult

Substances

  • Enzyme Inhibitors
  • Vasodilator Agents
  • Nitric Oxide
  • Folic Acid
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III