For the first time, researchers identified sex-based differences in genetic expression of human pulmonary microvascular endothelial cells (HPMECs).
Results from a study published in Physiological Genomics revealed important sex-based differences between male and female human pulmonary microvascular endothelial cells (HPMECs). These findings demonstrate a potential driving factor in the sexual dimorphism that arises in forms of pulmonary hypertensive disease.
Previously, sexual dimorphism has been observed in cases of pulmonary hypertension (PH). PH is a disease that exhibits degrees of sex-based differences, which can be observed in the higher likelihood females have for developing this disease, as well as the higher survival rates females have compared with their male counterparts. The authors of the present study note that past studies evaluating the underlying mechanisms in these discrepancies have been centered on function of sex hormones; however, sex chromosomes and sex-based differences occurring in adult HPMECs have not been sufficiently evaluated in PH.
To address this gap in knowledge, researchers conducted a study to investigate sex-based differences in the human pulmonary microvascular endothelium. They evaluated endothelial cellular responses to normoxia and hypoxia, hypothesizing that HPMEC responses and differences would occur independently of those observed in sex hormone environments. Since human endothelial cells continually undergo shear stress, HPMECs from a limited number of healthy male and female donors (less than 10, with later additions as more donors became available) were cultured under physiological shear stress conditions. Additionally, these samples were analyzed with label-free quantitative proteomics and RNA sequencing.
Of the differentially expressed genes (DEG) in female and male HPMECs—evaluated in normoxia and hypoxia—researchers found the most notable differences expressed in Y-chromosome encoded genes that have been potentially indicated in the development of PH: RPS4Y1, DDX3Y, UTY, ZFY and 228 PRKY. As for X-encoded genes, the most distinguishable difference was detected in the expression of XIST—which was more highly expressed in female HPMECs compared with male. In this assessment, no notable differences were observed in the proteomic analysis on proteins encoded by sex chromosomes.
To identify enriched genetic pathways differentiating the sexes, researchers used a Gene Set Enrichment Analysis (GSEA). After 24 hours of normoxia, the analysis revealed that 3 gene sets in male HPMECs were enriched, compared with 13 in female HPMECs. After 48 hours of normoxia, 3 gene sets in male samples compared with 8 in female samples were enriched. Following 24 hours of hypoxia, researchers found 2 gene sets of male HPMECs enriched compared with 20 in female HPMECs. Responses after 48 hours of hypoxia showed 2 gene sets in male samples and 19 in female samples enriched. Subsequently, researchers conducted this experiment in vitro and observed that male cells had increased proliferation rates compared with female cells in normoxic conditions.
Overall, these results demonstrate, for the first time, that sex-based differences occur in the cellular pathways in the human pulmonary microvascular endothelium—in both RNA and protein expression, as well as normoxic and hypoxic conditions. Most importantly, the authors emphasize, these distinct expressions occurred in HPMECs that were cultured outside of a sex hormone environment.
“Culturing of cells isolated from male and female donors in the absence of the sex hormones is a straightforward model for investigating the sex chromosomal influence on the sex differences,” the authors state, “however, this method does not allow complete elimination of the impact of the sex hormones. Sex hormones have a long-lasting programming effect on cells (82) and the absence of the sex hormones can only eliminate the acute actions of differences in the sex hormone environment to which the cells were exposed prior to isolation.”
They recommend further studies, with large sample sizes, to better understand the association between sex-based differences, pulmonary microvasculature remodeling, and the heighted vascular resistance indicated in the development of PH.
Reference
Kostyunina DSl, Pakhomov NV, Jouida A, Dillon E, Baugh JA, McLoughlin P. Transcriptomics and proteomics revealed sex differences in human pulmonary microvascular endothelial cells. Physiol Genomics. 2023 Dec 4. doi: 10.1152/physiolgenomics.00051.2023
Real-World Data Show Sotorasib Effective for NSCLC With KRAS Mutation
May 18th 2024Data from real-world and clinical-trial settings on frontline monotherapy treatment with the KRAS inhibitor sotorasib both show similar progression-free survivals and a high likelihood that the treatment’s efficacy is not affected with dose reduction.
Read More
Health Equity and Access Weekly Roundup: May 18, 2024
May 18th 2024The US Senate hosted a panel addressing physician and health care shortages and efforts to increase minority representation in the medical field. An expert discussed initiatives to prevent senior homelessness. Advocates called for the repeal of the Comstock Act. Regulatory reforms are called for to improve rural cancer patients' access to pharmacies. Research reveals the impact of denials on patient access to immunology treatments.
Read More
Frameworks for Advancing Health Equity: Urban Health Outreach
May 9th 2024In the series debut episode of "Frameworks for Advancing Health Equity," Mary Sligh, CRNP, and Chelsea Chappars, of Allegheny Health Network, explain how the Urban Health Outreach program aims to improve health equity for individuals experiencing homelessness.
Listen
Study Highlights Significant Increases in Utilization, Spending on DMD Drugs in Medicaid
May 17th 2024The findings add to recent research on the growing utilization, expenditure, and prices of Duchenne muscular dystrophy (DMD) therapies in the current landscape, an area health care policy could potentially address.
Read More