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Gender Difference on the Cellular Level: Distinct Stress Responses in Male and Female Endothelial Cells Isolated From Mouse Lungs

Olga Rafikova

Marina Zemskova

Sergey Kurdyukov

Ruslan Rafikov

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1005

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Background

Pulmonary arterial hypertension (PAH) is a disease with a well-established sexual dimorphism. While females generally being associated with higher susceptibility to PAH, males are showing lower survival rate and predisposition to develop RV failure. Sex hormones mediated gender difference is well described for many vascular diseases, including PAH. In this study, we investigated whether the contribution of gender goes beyond the effects of sex hormones by comparing the profile of pulmonary endothelial cells isolated from both genders.

Methods

Mouse lung endothelial cells (MLEC) were obtained from male and female 8 wk old mice using positive selection with anti-PECAM-1 antibody conjugated to Dynabeads and cultured for 3 passages. After 3th passage, MLEC were additionally purified by a second positive selection using ICAM2 antibody and validated by FACS analysis with anti-CD31-FITS antibody, which yields 98% pure population of MLEC. Gender difference in the MLEC omitted from effects of sex hormones was analyzed by evaluation of cell morphology, proliferation rate, mitochondrial function, and capability to tolerate the stress.

Results

Male MLEC were found to be smaller in size and possessed about 2 times higher rate of proliferation comparing to female. The level of mitochondrial polarization was also higher in male cells, suggesting an increased cellular energy and metabolic output associated with male gender that could be also responsible for the higher proliferative state. Exposure of cells to 2% hypoxia for 24 hours induced a strong apoptotic response in female but not male MLEC. In contrast, treatment with mitochondrial respiratory Complex III inhibitor Antimycin A (AA) mediated a severe necrosis specifically in male MLEC, while female cells responded again primarily by apoptosis. Taken together these results suggest that male cells appeared to be protected against the mild stress conditions, possibly due to an increased mitochondrial biogenesis. In contrast, female cells are protected against more damaging stimuli, such as mitochondrial dysfunction. Indeed, the apoptotic response to AA in females was similar to hypoxia. Besides, apoptosis as a controlled and immune silent type of cell death represents a more physiological response to stress compared to necrosis.

Conclusions

This study revealed that isolated and cultured pulmonary endothelial cells retain a gender difference even in the absence of sex hormone stimulation, suggesting the importance of genetic mechanisms in gender dimorphism. The discovered difference in the ability to tolerate the stress is of a great importance for the PAH known to be closely associated with different types of stress conditions, including hypoxia and mitochondrial dysfunction.