A nutraceutical timing hypothesis: Does supplementation with nitrate-rich beetroot juice provide vascular protection across postmenopausal stages?
Open Access
- Author:
- Delgado, Jocelyn
- Graduate Program:
- Integrative and Biomedical Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 23, 2024
- Committee Members:
- Gregory Shearer, Program Head/Chair
Joshua Kellogg, Outside Unit Member
Mary Jane De Souza, Major Field Member
David Proctor, Chair & Dissertation Advisor
Kristina Petersen, Outside Field Member - Keywords:
- Menopause
Endothelium
Dietary Nitrate
Vascular
Ischemia-Reperfusion Injury
Nitric Oxide - Abstract:
- Differentiating the adverse chronological- and reproductive-aging associated changes on the vasculature remains a challenge to investigate. This is particularly important for women as the onset of menopause coincides with unfavorable changes to cardiovascular disease (CVD) risk factors. The permanent loss of estrogen following menopause is associated with reductions in nitric oxide bioavailability (NO), an important vasodilator and signaling molecule, which can lead to impaired endothelium-dependent vasodilation. Endothelial dysfunction, a prognostic indicator of CVD risk, rapidly declines across the menopause transition, independent of chronological age. To further understand the effects of reproductive aging on the vasculature, the first study of this dissertation compared the extent of vascular dysfunction from pneumatic cuff-induced whole arm endothelial ischemia-reperfusion (IR) injury in estrogen-replete premenopausal (n=11) and estrogen-deficient postmenopausal women staged into early- (1-6 years following menopause, n=11) and late- (6+ years following menopause, n=11) postmenopause. In this cross-sectional study, we found that despite comparable baseline endothelial function to premenopausal women, early postmenopausal women demonstrate an exaggerated IR-induced impairment in endothelial function. Few low risk-estrogen therapies exist for enhancing vascular health, and traditional pharmacological management of CVD risk factors are less effective in older women. Consequently, there is a clinical demand to investigate innovative non-pharmacological interventions, specifically nutraceuticals, focusing on dietary strategies that can enhance NO bioavailability in postmenopausal women. The subsequent study comprising this dissertation tested the ability of both acute (600 mg nitrate per 140 mL x one dose) and 7-day (300 mg nitrate per 70mL daily x 7 days) nitrate-rich beetroot juice supplementation to raise circulating concentrations of nitrite and favorably influence resting endothelial function, endothelial protection (i.e., endothelial resistance) against IR injury, and plasma oxidative stress (chapter 5) in normotensive, metabolically healthy early- (n=12) and late- (n=12) postmenopausal women. A randomized, placebo-controlled (BRnitrate vs. BRplacebo; IND#119978), double blind, crossover study design was used, with a minimum 14-day washout period between treatments and standardized pre-visit instructions to minimize between-visit variation in plasma nitrite concentration. Compared to responses observed with BRplacebo, our findings demonstrate: 1) acute BRnitrate consumption raised plasma nitrite concentration and improved endothelial resistance against IR injury, regardless of postmenopausal stage, 2) despite a clinically significant increase in resting endothelial function, nitrate-mediated endothelial protection against IR injury was not maintained 24-hours following the last dose of 7-day supplementation with BRnitrate in either postmenopausal group and 3) while 7-day BRnitrate did not affect the plasma metabolome, we show that reproductive aging critically impacts the plasma metabolite profile between postmenopausal stages. Collectively, these results provide the first evidence that acute dietary nitrate supplementation enhances endothelial protection against IR injury, regardless of postmenopausal stage. Moreover, our findings highlight that chronobiological variations in nitrate metabolism and the timing of BRnitrate supplementation in relation to the IR injury protocol, may have confounded the observed results following 7-day BRnitrate supplementation. These studies also raise a new series of questions related to the mechanisms by which dietary nitrate may benefit postmenopausal cardiovascular health and support the pursuit of larger scale trials of dietary nitrate supplementation to determine whether these effects are in fact clinically significant and sustainable.