Sex-Specific Differences in Endothelial Function Are Driven by Divergent Mitochondrial Ca²⁺ Handling

Area of Science:

• Cardiovascular Physiology
• Mitochondrial Biology
• Endothelial Function

Background:

• Sex-specific differences in vasodilation are partly due to cytosolic calcium (Ca2+) handling variations.
• The role of mitochondrial Ca2+ handling in these sex differences in vascular reactivity is not well understood.

Purpose of the Study:

• To investigate the contribution of mitochondrial Ca2+ entry via the mitochondrial Ca2+ uniporter (MCU) to sex differences in resistance artery vasoreactivity.
• To explore the influence of estradiol on endothelial cell Ca2+ handling and mitochondrial function.

Main Methods:

• Utilized genetic models of endothelial MCU ablation in mice to assess vasodilation responses.
• Performed ex vivo Ca2+ imaging of mesenteric arteries using Fura-2AM to measure cytosolic Ca2+ transients.
• Investigated the effects of MCU inhibition and estradiol treatment on cultured human aortic endothelial cells.

Main Results:

• Endothelial MCU ablation exacerbated the reduction in acetylcholine-induced vasodilation in female mice compared to males.
• Female mice showed higher cytosolic Ca2+ transients in response to acetylcholine, which were sensitive to MCU inhibition.
• Estradiol treatment enhanced endothelial cell Ca2+ transients, buffering capacity, and mitochondrial Ca2+ uptake, increasing mitochondrial mass, fusion, and membrane potential, while reducing superoxide production.

Conclusions:

• Mitochondrial function in endothelial cells exhibits sex-specific differences, with females possessing enhanced Ca2+ uptake capacity.
• These sex differences are primarily attributed to a greater mitochondrial mass and higher mitochondrial membrane potential in females.
• The composition of the mitochondrial Ca2+ uniporter complex does not appear to be the basis for these observed sex differences.