Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone 2023 Wilson et al

[Andy]

Abstract

Arteries and veins are lined by nonproliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis, rather than mitochondrial oxidative phosphorylation, to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells, and little is known about energy production in endothelial cells within the fully formed vascular wall.

Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial respiration disrupts endothelial control of vascular tone. Basal, mechanically activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. Agonist-evoked calcium activity was also inhibited by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for mitochondria in endothelial cell energy production is independent of species, sex, or vascular bed.

These data show that a mitochondrial ATP supply is necessary for calcium-dependent, nitric oxide-mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.

Open access, https://academic.oup.com/function/article/4/2/zqac063/6886541

 

[SNT Gatchaman]

A potential direct link between abnormal metabolic pathways and endothelial dysfunction / orthostatic intolerance. Some summary quotes, re-ordered —

Remarkably, despite ECs having abundant access to high concentrations of oxygen in the blood, four decades of reports have indicated that they use glycolysis for ATP production rather than mitochondrial oxidative phosphorylation.

Mammalian cells generally rely on mitochondrial respiration to fuel bioenergetic processes, but ECs are considered to be an exception to this rule.

This estimation has emerged from studies examining the angiogenic potential of cultured proliferative/migratory ECs. However, the majority of ECs in perfused blood vessels are neither proliferative nor migratory (eg, less than 2% of ECs in liver and spleen have a proliferative phenotype). Yet, from data derived from cultured proliferative/migratory ECs, it is assumed that “quiescent” ECs are also glycolytic and that mitochondrial-derived ATP plays little role in regulating endothelial function. In stark contrast to this assumption, we provide clear evidence that mitochondrial ATP production is crucial for the most widely known function of ECs in mature blood vessels - the control of artery diameter.

Recent findings have placed considerable emphasis on this prevailing, but potentially incomplete, view of mitochondria as a minor source of ATP production in ECs.

Together, these studies suggest that endothelial mitochondria do play an important role in vascular function. However, the significance of mitochondrial metabolism has rarely been studied outside of the context of proliferative ECs in angiogenesis or pulmonary hypertension, in which the contribution of the organelle may be diminished. Moreover, almost no attention has been given to the energetic requirements of perfused blood vessel ECs.

Our results provide evidence that mitochondrial energy production in ECs critically regulates blood vessel diameter. Moreover, mitochondrial energy production is far more intimately linked to EC physiology than is currently appreciated.

Our work highlights the idea that arterial ECs require mitochondrial respiration for the control of vascular tone and suggests that aberrant mitochondrial energy production may underlie endothelial dysfunction. As such, therapeutic intervention to promote EC mitochondrial energy production may be an effective strategy to combat vascular dysfunction in a range of diseases.