Journal article
Sex‐Specific Differences in Endothelial Function Are Driven by Divergent Mitochondrial Ca 2+ Handling
Journal of the American Heart Association, Vol.11(13), e023912
07/05/2022
DOI: 10.1161/JAHA.121.023912
PMCID: PMC9333382
PMID: 35766269
Abstract
Background
Sex‐specific differences in vasodilation are mediated in part by differences in cytosolic Ca2+ handling, but how variations in mitochondrial Ca2+ contributes to this effect remains unknown. Here, we investigated the extent to which mitochondrial Ca2+ entry via the MCU (mitochondrial Ca2+ 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 Ca2+ imaging of mesenteric arteries with Fura‐2AM confirmed higher cytosolic Ca2+ transients triggered by ACh in arteries from female mice versus male mice. MCU inhibition both strongly reduced cytosolic Ca2+ transients and blocked mitochondrial Ca2+ entry. In cultured human aortic endothelial cells, treatment with physiological concentrations of estradiol enhanced cytosolic Ca2+ transients, Ca2+ buffering capacity, and mitochondrial Ca2+ entry in response to ATP or repeat Ca2+ 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 Ca2+ 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.
Details
- Title: Subtitle
- Sex‐Specific Differences in Endothelial Function Are Driven by Divergent Mitochondrial Ca 2+ Handling
- Creators
- Celio Damacena de Angelis - University of IowaBenney T. Endoni - University of IowaDaniel Nuno - University of IowaKathryn Lamping - University of IowaJohannes Ledolter - University of IowaOlha M. Koval - University of IowaIsabella M. Grumbach - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.11(13), e023912
- DOI
- 10.1161/JAHA.121.023912
- PMID
- 35766269
- PMCID
- PMC9333382
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Language
- English
- Date published
- 07/05/2022
- Academic Unit
- Statistics and Actuarial Science; Cardiovascular Medicine; Radiation Oncology; Business Analytics; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984360041502771
Metrics
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