| An age-related reduction in tetrahydrobiopterin (BH4) bioavailability is a common mechanistic link that contributes to the decline in reflex cutaneous vasodilation (VD) and vasoconstriction (VC) with age. Intervention strategies that increase the bioavailability of BH4 may be capable of restoring vessel function in the older cutaneous vasculature. Therefore, the purpose of this series of studies was to examine the efficacy of oral intervention strategies that could potentially increase bioavailable BH 4 in improved reflex cutaneous VD and VC in a healthy, older population. In the first set of studies, we hypothesized that acute oral sapropterin (Kuvan RTM, shelf-stable pharmaceutical formulation of BH4) would acutely augment reflex VD and VC in aged skin through nitric oxide (NO)-mediated and adrenergic mechanisms, respectively. Oral sapropterin acutely increased bioavailable BH4 in aged skin microvasculature sufficiently to (1) increase NO-dependent dilation and restore reflex VD, and (2) increase both reflex and pharmacologically-induced VC through adrenergic mechanisms. In a follow up study, we tested a chronic sapropterin intervention in 4 older adults. The results of this proof-of-concept study suggest that chronic sapropterin augments reflex VD in older human skin. However, there was not sufficient evidence to suggest efficacy in improved reflex VC in the same population. Collectively, these findings suggest that sapropterin acutely restores vessel function in healthy, older adults and that chronic sapropterin may be a viable intervention for improved vascular function in this population. Finally, we hypothesized that chronic folic acid supplementation, which increases endogenous BH4 bioavailability, would augment reflex VD in aged skin. Folic acid (5mg/daily for 6 weeks) increased reflex VD in healthy, older cutaneous microvasculature through NO-dependent mechanisms. These findings suggest that folic acid treatment may be an effective intervention strategy for improved vascular endothelial function in older adults. Taken together, this series of studies suggests that oral intervention strategies that increase BH 4 bioavailability are capable of restoring cutaneous vascular function in healthy, older adults. |
