Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

Abstract

The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH(4)), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH(4). Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal (n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH(4). Subsequently, in postmenopausal women, vascular testing (before and after BH(4)) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH(4) administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm(2)·mmHg(-1)·10(-1) vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm(2)·mmHg(-1)·10(-1), P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH(4), possibly because estrogen increased BH(4) bioavailability. Carotid artery compliance and FMD increased with BH(4) in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH(4) may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone.

Figures

Fig. 1.

Carotid artery compliance before and after oral tetrahydrobiopterin (BH4) administration in premenopausal and postmenopausal women. Data are reported as means ± SE. *P < 0.0001 vs. premenopausal women. †P < 0.001 vs. baseline of the same group.

Fig. 2.

Brachial artery flow-mediated dilation (FMD) before and after oral BH4 administration in premenopausal and postmenopausal women. Data are reported as means ± SE. *P < 0.0001 vs. premenopausal women. †P < 0.001 vs. baseline of the same group.

Fig. 3.

Carotid artery compliance at baseline and following transdermal placebo or estradiol (E2) and after oral BH4 administration in postmenopausal women. Data are reported as means ± SE. *P < 0.001 vs. placebo women.

Fig. 4.

Brachial artery FMD at baseline and following transdermal placebo or estradiol, and after oral BH4 administration in postmenopausal women. *P < 0.001 vs. placebo women. †P < 0.001 vs. baseline of the same group.