Sex‐Specific Differences in Endothelial Function Are Driven by Divergent Mitochondrial Ca 2+ Handling
Open accessAbstract
Background Sex‐specific differences in vasodilation are mediated in part by differences in cytosolic Ca 2+ handling, but how variations in mitochondrial Ca 2+ contributes to this effect remains unknown. Here, we investigated the extent to which mitochondrial Ca 2+ entry via the MCU (mitochondrial Ca 2+ uniporter) drives sex differences in vasoreactivity in resistance arteries. Methods and Results Enhanced vasodilation of mesenteric resistance arteries to acetylcholine (ACh) was reduced to larger extent in female compared with male mice in 2 genetic models of endothelial MCU ablation. Ex vivo Ca 2+ imaging of mesenteric arteries with Fura‐2AM confirmed higher cytosolic Ca 2+ transients triggered by ACh in arteries from female mice versus male mice. MCU inhibition both strongly reduced cytosolic Ca 2+ transients and blocked mitochondrial Ca 2+ entry. In cultured human aortic endothelial cells, treatment with physiological concentrations of estradiol enhanced cytosolic Ca 2+ transients, Ca 2+ buffering capacity, and mitochondrial Ca 2+ entry in response to ATP or repeat Ca 2+ boluses. Further experiments to establish the mechanisms underlying these effects did not reveal significant differences in the expression of MCU subunits, at either the mRNA or protein level. However, estradiol treatment was associated with an increase in mitochondrial mass, mitochondrial fusion, and the mitochondrial membrane potential and reduced mitochondrial superoxide production. Conclusions Our data confirm that mitochondrial function in endothelial cells differs by sex, with female mice having enhanced Ca 2+ uptake capacity, and that these differences are attributable to the presence of more mitochondria and a higher mitochondrial membrane potential in female mice rather than differences in composition of the MCU complex.
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17β-estradiol regulates multiple other aspects of mitochondrial function through ERs, including ROS generation, antioxidant defense, and Ca2+ handling.
“Moreover, 17β-estradiol also appears to regulate multiple other aspects of mitochondrial function through ERs, including ROS generation, antioxidant defense, and Ca2+ handling (126–131).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [131]
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- Authors
- Damacena de Angelis, C., Endoni, B. T., Nuno, D., Lamping, K., Ledolter, J., Koval, O. M., & Grumbach, I. M.
- Affiliations
- Department of Internal Medicine, Abboud Cardiovascular Research Center University of Iowa Iowa City IA
- University of Iowa (US)
- Corresponding author
- Koval, Olha M.
- Grumbach, Isabella M.
- Venue
- Journal of the American Heart Association
- Published
- 2022-07-05
- Volume
- 11
- Issue
- 13
- Pages
- e023912-e023912
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC9333382
- OpenAlex
- W4283691688
- Cited by
- 17
- References
- 51
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 4
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000163)
- National Heart, Lung, and Blood Institute (R01HL108932)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- sex differences, endothelial function, mitochondrial calcium handling, mitochondrial calcium uniporter, cytosolic calcium transients, vasodilation, resistance arteries, estradiol, mitochondrial fusion, mitochondrial membrane potential, mitochondrial superoxide, mitochondrial mass, acetylcholine
- MeSH terms
- Animals, Calcium, Estradiol, Female, Humans, Male, Mitochondria, Sex Characteristics, Calcium Channels, Endothelial Cells, Mice
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