Dietary flavanols: A potential strategy to combat prolonged sitting‐induced vascular dysfunction?

Sitting for prolonged periods is a significant risk factor for the development of cardiovascular disease (CVD). The mechanisms linking prolonged sitting and CVD are not fully understood. An acute bout of prolonged uninterrupted sitting is commonly used to examine the negative physiological effects of prolonged sitting on cardiovascular health. Laboratory-based studies have demonstrated that a single bout of prolonged sitting can attenuate macro- and microvascular function, especially in the lower limb (Ferreira-Santos et al., 2024). Of note, such impairments are considered early markers of atherosclerosis and vascular disease. Therefore, strategies to prevent sitting-induced disruptions in vascular function have become an area of interest as a way to reduce CVD risk. Physical activity-based strategies (e.g. prior aerobic exercise, fidgeting) have been relatively well studied in the past 10 years, yet nutritional strategies have been largely understudied. In a recent article published in The Journal of Physiology, Daniele et al. (2025) investigated the impact of dietary flavanols on upper- and lower-limb vascular responses to an acute bout of prolonged sitting, with a counterbalanced, double-blinded, placebo-controlled design in 40 young, healthy men. Cardiorespiratory fitness level was assessed via a cycle ergometer-based maximal oxygen consumption (i.e. V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_2}{\mathrm{peak}}}}$ ) test. Participants were equally allocated to either ‘high fit’ ( V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_2}{\mathrm{peak}}}}$ ≥ 49 ml/kg/min) or ‘low fit’ ( V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_2}{\mathrm{peak}}}}$ ≤ 41 ml/kg/min). Brachial and superficial femoral artery (macrovascular) endothelial function was assessed using a non-invasive ultrasound-based flow-mediated dilatation (FMD) assessment, which consists of a 1-min baseline, 5-min distal cuff occlusion at 220 mmHg and 5-min postocclusion recording. Additionally, calf skeletal muscle resistance vessel (microvascular) haemodynamics was assessed in the leg using near-infrared spectroscopy during the FMD protocol to capture arterial occlusion-induced reactive hyperaemia and resting microvascular haemodynamics. Before the 2-h sitting protocol, participants in both fitness groups consumed either a high-flavanol (150 mg (−)-epicatechin) or a low-flavanol (<6 mg (−)-epicatechin) cocoa beverage. As expected, after 2 h of uninterrupted sitting, participants in the low-flavanol condition exhibited significant declines in brachial and superficial femoral artery FMD, regardless of their fitness level. In contrast, FMD in both arteries was preserved after high-flavanol intake in both high- and low-fit individuals. At the microvascular level, prolonged sitting impaired calf reactive hyperaemia (lower magnitude of oxygen reperfusion and slower recovery) after both low- and high-flavanol interventions. Furthermore, prolonged sitting resulted in significant declines in blood flow and shear rate in both the brachial and superficial femoral arteries, regardless of flavanol condition. Of note, reduced blood flow and shear stress are thought to be key mechanisms contributing to sitting-induced endothelial dysfunction. Thus, these findings suggest that high-flavanol cocoa protects conduit artery endothelial function during prolonged sitting, independent of effects on blood flow. However, high-flavanol cocoa failed to provide protection against sitting-induced microvascular dysfunction. Vascular protective effects of flavonoids are well documented, particularly at the level of the vascular endothelium (Monahan et al., 2011). Prolonged sitting-induced declines in FMD are interpreted as reflecting diminished nitric oxide (NO) bioavailability and conduit artery endothelial dysfunction, which are thought to be driven largely by reductions in blood flow and shear stress (Ferreira-Santos et al., 2024). Such disturbed flow and shear profiles can promote oxidative stress, increase endothelin-1 release and upregulate vascular inflammatory signalling, thereby diminishing NO bioavailability. Human studies have shown that cocoa flavanols can enhance NO-mediated vasodilatation by increasing endothelial NO synthase activity within 1–2 h of ingestion (Monahan et al., 2011). Of note, the superficial femoral artery FMD protocol used by Daniele et al. (2025) is known to be predominantly NO mediated. Collectively, these findings support the hypothesis that improved NO bioavailability (rather than changes in resting haemodynamics per se) is a key mechanism underlying the protective effects of cocoa flavanols on conduit artery (macrovascular) function during prolonged sitting. Consistent with this interpretation, prior beetroot juice ingestion, which contains high levels of dietary nitrate and enhances NO bioavailability via the nitrate-nitrite-NO pathway, has also been demonstrated to prevent sitting-induced endothelial dysfunction assessed by FMD (Morishima et al., 2022). Interestingly, although cocoa flavanols exert protective effects on the macrovasculature, they had no effect on sitting-induced lower-limb resistance vessel (microvascular) dysfunction, as assessed by the calf reactive hyperaemia response during the FMD protocol. This divergence is physiologically plausible. Although direct evidence in the lower limb is limited, ischaemia-induced reactive hyperaemia in the upper-limb microvasculature appears to be only minimally NO mediated and is driven largely by local metabolic vasodilators and ion channel-mediated mechanisms (e.g. endothelium-derived hyperpolarizing factors acting via potassium channels) rather than endothelial NO. Moreover, beyond the acute vasodilatory impairment captured by reactive hyperaemia, prolonged sitting may induce early structural adaptations in resistance vessels that are unlikely to be attenuated or prevented by an acute flavanol dose. As proposed by Ferreira-Santos et al. (2024), prolonged sitting results in vasoconstriction of resistance vessels, which may be attributed to the low metabolic demand of inactive skeletal muscle, venous pooling, sympathetic activation and/or arterial bending. Consistent with this, Daniele et al. (2025) observed significant declines in resting microvascular tissue oxygenation in the medial gastrocnemius within the first 10 min of sitting, suggesting reduced oxygen delivery to the muscle and increased local vascular resistance. The prolonged vasoconstriction of resistance vessels may initiate early, subcellular structural changes in the arterial wall, such as actin polymerization in vascular smooth muscle cells, during a single bout of sitting (Ferreira-Santos et al., 2024). It is likely that a single high-dose cocoa flavanol intervention is not sufficient to prevent such structural changes. Because prolonged intake of cocoa flavanols has been shown to alleviate structural changes in blood vessels (e.g. arterial stiffness) (Okamoto et al., 2016), it is possible that chronic cocoa flavanol supplementation could mitigate sitting-induced structural adaptations. This hypothesis represents an important direction for future research. Prolonged sitting may also increase muscle sympathetic nerve activity (Ferreira-Santos et al., 2024), which could diminish vasodilatory function through competing α-adrenergic vasoconstriction. Of note, Daniele et al. (2025) showed that diastolic blood pressure consistently increased after 2 h of sitting, regardless of low- or high-flavanol intervention. Although an acute increase in blood pressure is an indirect marker of sympathetic activation, a sustained increase in diastolic blood pressure during sitting supports the hypothesis of augmented sympathetic tone and suggests that dietary flavanols did not attenuate this response. Because resistance vessels have a higher density of α-adrenergic receptors and denser sympathetic innervation than conduit arteries, sympathetic activation is likely to play a more important role in sitting-induced microvascular dysfunction. Consistent with this speculation, acute sympathetic activation has been shown to blunt the hyperaemic response to passive leg movement in young males (Hanson et al., 2025). Collectively, it is plausible that increased sympathetic vasoconstrictor effects during sitting override the NO-mediated benefits of dietary flavanols at the level of resistance vessels. Resistance vessels are a vulnerable target in the development of CVD. To the best of our knowledge, no non-physical activity-based (active or passive) intervention has been shown to effectively prevent sitting-induced resistance vessel dysfunction. This represents an important future research direction, as there are likely divergent mechanisms contributing to macrovascular and microvascular dysfunction during sitting (Ferreira-Santos et al., 2024). Daniele et al. (2025) provide an excellent example that a single mitigation strategy may not be equally effective across the entire vasculature. Collectively, it remains unclear whether there is a nutritional strategy that is sufficient to protect microvascular function or whether such approaches will need to be combined with physical activity-based interventions to fully preserve both conduit and resistance vessel function. Daniele et al. (2025) offer novel insight into the potential of dietary flavanols to reduce the detrimental effects of prolonged sitting on vascular function in both low- and high-fit individuals, who appear similarly susceptible to sitting-induced vascular dysfunction. Although most previous studies have demonstrated the effectiveness of physical activity-based strategies, dietary flavanols represent a unique and highly accessible mitigation approach, particularly for individuals with physical or environmental ambulatory constraints (e.g. injury, long-duration travel), where more traditional options such as walking breaks or exercise may not be feasible. Future research should test the ecological validity of dietary flavanols by examining whether long-term intake in free-living settings can protect vascular function against the detrimental effects of prolonged sitting, particularly in high-risk populations such as individuals with mobility limitations. Finally flavanols were shown to only preserve conduit artery endothelial function and not prevent sitting-induced impairments in resistance vessel function or increases in blood pressure (Daniele et al., 2025). Therefore, although dietary flavanols are a promising strategy, we still encourage individuals to break up long periods of sitting as often as possible to mitigate the health risks associated with prolonged sitting. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors have no conflicts of interest to report. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.