par Nutrimuscle-Conseils » 14 Fév 2024 13:07
Novel insights into an old story: Magnesium and vascular tone
Jeanette A. Maier Acta Physiologica 05 February 2024
The study by Kudryavtseva et al1 sheds new light on the mechanisms underlying the regulation of blood pressure by magnesium and supports the qualified health claim released by the FDA regarding the relationship between a reduced risk of high blood pressure and the content of magnesium in conventional foods and dietary supplements.2
Vascular tone results from the contractility of vascular smooth muscle cells within arteries and arterioles. It serves as the primary factor influencing resistance to blood flow in the circulation, thereby controlling the levels of blood pressure. Under physiological conditions, vascular tone reflects the precise equilibrium between factors that induce relaxation and contraction. Before delving into the new mechanisms described by the authors, let us briefly explore the complex world of vascular tone regulation, where the endothelium, the thin monolayer lining all the vessels, plays a principal role. Endothelial cells generate vasodilators, such as prostacyclin (PGI2) and nitric oxide (NO). Rather than PGI2 which is mainly released luminally, it is NO synthesized by the constitutively activated endothelial NO synthase that plays a relevant role in the regulation of vascular tone,3 especially in conduit arteries. NO stimulates the formation of cyclic GMP, thus activating protein kinase G, which reduces intracellular calcium and, therefore, inhibits calcium-induced smooth muscle contraction during depolarization.3
An increasing body of experimental data highlights the existence of an endothelium-derived vasodilatory mechanism, distinct from nitric oxide and prostacyclin, which acts mainly on small resistance arteries.4 Its identity remains currently elusive and is commonly referred to as endothelium-derived hyperpolarization factor (EDHF) by researchers proposing that EDHF is chemical entity not yet characterized at the molecular level capable of increasing intracellular calcium levels. This, in turn, seems to trigger the opening of calcium-activated potassium channels in endothelial and vascular smooth muscle cells, thus causing an endothelium-dependent hyperpolarization of smooth muscle cells.4 Instead of considering a diffusible factor as responsible for smooth muscle hyperpolarization, it is also plausible that hyperpolarizing currents propagate from the endothelium to the smooth muscle via myoendothelial gap junctions situated on endothelial projections.5 These gap junctions, particularly abundant in resistance arteries, represent bidirectional signaling microdomains that govern heterocellular cross-talk and regulate vasoreactivity.
The relevance of NO and EDHF/hyperpolarizing currents in regulating vasoreactivity is underscored by evidence indicating that vasorelaxation mediated by these mechanisms is impaired in hypertension.
Numerous studies have shown the relevance of maintaining magnesium homeostasis to optimize blood pressure levels. These studies propose beneficial effects of magnesium on vascular tone, attributed to its role in balancing endothelial and smooth muscle function. The novelty of Kudryavtseva's article lies in revealing the involvement of various endothelium-dependent or independent signaling pathways in magnesium-driven vasorelaxation ex vivo and in vitro in a murine model. In brief, the authors demonstrate that:
Magnesium stimulates endothelial-dependent vasodilation by inducing the synthesis of NO and EDHF in mouse aortas and mesenteric arteries in a dose-dependent fashion. Both EDHF and NO contribute to magnesium regulation of vascular tone. Although magnesium stimulates PGI2 synthesis, PGI2 does not exert any effect on vascular tone;
Endothelial-dependent acetylcholine-induced vasodilation, primarily mediated by NO, demonstrates a direct proportionality to the concentration of magnesium;
Physiological concentrations of magnesium more effectively counteract α1 receptor-mediated contraction than depolarization-mediated contraction;
Elevating extracellular potassium, that is, inhibiting hyperpolarizing potassium current, diminishes magnesium-induced relaxation in the mouse aorta;
In endothelium-denuded aortas, magnesium promotes smooth muscle cell relaxation also when intracellular calcium is high, possibly because of the well-known calcium–magnesium antagonism. Accordingly, high extracellular calcium reverses magnesium-induced vasorelaxation. Furthermore, the transporter for divalent cations TRPM7 does not seem to play a role in magnesium-induced vasodilation, as demonstrated by two genetic mouse models that lack TRPM7 in vascular smooth muscle cells.
These findings contribute valuable insights for interpreting clinical reports that suggest an inverse correlation between dietary magnesium intake and the prevalence of arterial hypertension. A recent analysis of data from the 2007–2018 National Health and Nutrition Examination Survey (NHANES), a nationally representative cross-sectional survey of health in the United States, revealed an independent, negative, and significant correlation between magnesium intake and the prevalence of hypertension.6
As highlighted by Kudryavtseva et al, further research is warranted in both experimental models and humans. Unraveling the chemical identity, if any, of magnesium-regulated EDHF and investigating the impact of varying magnesium concentrations on the structure and function of myoendothelial gap junctions pose significant challenges. Additionally, exploring age- and sex-related differences in magnesium-driven endothelium-dependent and independent regulation of vascular tone would be intriguing.
Magnesium plays a pivotal role in various physiological functions, encompassing metabolic pathways, redox balance, and the modulation of inflammatory responses, to name a few. Dysregulation of these fundamental processes is implicated in the pathogenesis of chronic non-communicable diseases, the principal determinants of disability and mortality globally. Notably, over the past 50 years, developed countries have witnessed a substantial decline in magnesium intake due to increased consumption of processed foods and filtered water. At a global scale, the excessive use of chemical fertilizers, pollution, and climate change deplete the soil of magnesium, yielding widespread consequences in the food chain.7
While these issues are indeed alarming and warrant urgent interventions, it is imperative to acknowledge that maintaining a balanced and nutritious diet, particularly one adhering to the principles of the Mediterranean diet, should facilitate adequate magnesium intake. Given the present constraints in understanding optimal magnesium levels and the challenges associated with standardizing serum magnesium reference ranges, supplementation might be advisable only when a magnesium deficiency is evident.
In conclusion, the work presented by Kudryavtseva et al1 enhances our understanding of magnesium's role in the regulation of vascular tone, offering intriguing insights for further exploration. This research holds the potential to contribute to the development of conclusive and consistent clinical guidance for the prevention and treatment of arterial hypertension.
