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Review
. 2017 Jan;75(1):61-70.
doi: 10.1093/nutrit/nuw053.

Role of folic acid in nitric oxide bioavailability and vascular endothelial function

Anna E Stanhewicz  1 , W Larry Kenney  2
Affiliations
Review

Role of folic acid in nitric oxide bioavailability and vascular endothelial function

Anna E Stanhewicz et al. Nutr Rev. 2017 Jan.

Abstract

Folic acid is a member of the B-vitamin family and is essential for amino acid metabolism. Adequate intake of folic acid is vital for metabolism, cellular homeostasis, and DNA synthesis. Since the initial discovery of folic acid in the 1940s, folate deficiency has been implicated in numerous disease states, primarily those associated with neural tube defects in utero and neurological degeneration later in life. However, in the past decade, epidemiological studies have identified an inverse relation between both folic acid intake and blood folate concentration and cardiovascular health. This association inspired a number of clinical studies that suggested that folic acid supplementation could reverse endothelial dysfunction in patients with cardiovascular disease (CVD). Recently, in vitro and in vivo studies have begun to elucidate the mechanism(s) through which folic acid improves vascular endothelial function. These studies, which are the focus of this review, suggest that folic acid and its active metabolite 5-methyl tetrahydrofolate improve nitric oxide (NO) bioavailability by increasing endothelial NO synthase coupling and NO production as well as by directly scavenging superoxide radicals. By improving NO bioavailability, folic acid may protect or improve endothelial function, thereby preventing or reversing the progression of CVD in those with overt disease or elevated CVD risk.

Keywords: 5-methyl tetrahydrofolate; endothelial function; folic acid; nitric oxide.

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Figures

Figure 1
Figure 1
Metabolism of folate. Abbreviations: 5-MTHF, 5-methyl tetrahydrofolate; MTHFR, 5,10-methylene tetrahydrofolate reductase; DHFR, dihydrofolate reductase; THF, tetrahydrofolate.
Figure 2
Figure 2
Schematic representation of nitric oxide synthesis. Nitric oxide synthase (NOS) requires adequate substrate (L-arginine) and cofactor (BH4) availability to remain in its coupled conformation and produce nitric oxide (NO). In conditions of limited substrate or cofactor bioavailability and/or high oxidative stress, NOS uncouples and produces superoxide (O2−) rather than NO. Abbreviations: BH4, tetrahydrobiopterin; NO, nitric oxide; NOS, nitric oxide synthase; O2−, superoxide; ONOO−, peroxynitrite; ROS, reactive oxygen species.
Figure 3
Figure 3
Proposed mechanisms by which 5-methyl tetrahydrofolate (5-MTHF) may increase nitric oxide (NO) synthesis and bioavailability. Abbreviations: 5-MTHF, 5-methyl tetrahydrofolate; BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; NO, nitric oxide; NOS, nitric oxide synthase; O2−, superoxide; ONOO−, peroxynitrite; ROS, reactive oxygen species.
Figure 4
Figure 4
Increased cutaneous vasodilation following oral sapropterin or folic acid administration in healthy older adults. Cutaneous vasodilation response to whole-body heat stress (increase in mean body temperature  =  1.0°C) in older adults following placebo and acute sapropterin (10 mg/kg body weight; n  =  9), chronic sapropterin (400 mg twice daily for 4 weeks; n  =  4), or chronic folic acid (5 mg once daily for 6 weeks; n  =  11). Adapted from Stanhewicz et al. and Stanhewicz et al.
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