Epidemiological statistics have long shown clear differences in heart disease prevalence between men and women. Younger women have lower rates of disease than men, but then, following menopause, the relative incidence climbs. As a result, heart disease rates are similar between men and women in their 50s and older. The data suggest that hormonal signals may contribute to the sex differences, but the biological mechanisms underlying them have remained unclear.
Recent advances in single cell research methods have made it possible to dissect the cellular composition of hearts in unprecedented detail. Teams led by Jackson Laboratory (JAX) Professor Nadia Rosenthal, Ph.D., F.Med.Sci, who also directs the research program at JAX’s Bar Harbor campus, have spearheaded this effort and revealed a complex mix of cells—structural, vascular, immune and others—present in heart tissue in addition to the predominant myocytes (contractile muscle cells). Now, in “Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones,” published in Cardiovascular Research, the researchers present findings of significant cellular differences between adult female and male mouse hearts.
The team, led by Rosenthal and senior author Alexander Pinto, Ph.D., now at the Baker Heart and Diabetes Research Institute in Melbourne (Australia), analyzed the relative abundance of endothelial cells (that line blood vessels), mesenchymal cells (involved with tissue regeneration and repair) and leukocytes (immune cells) and the subsets of cells within the larger categories. What they found was that while the absolute number of leukocytes and endothelial cells were similar in male and female mice, the female mice had a 1.6-fold greater number of mesenchymal cells than males.
When looking at cellular subsets, however, there were differences in all three categories. For example, a close look at leukocyte (immune) cell populations revealed that males have higher proportions of myeloid cells, granulocytes and B cells, while females have increases in natural killer cells, T cells and Undetermined non-myeloid cells. Interestingly, analyses of cellular populations at one and four weeks of age revealed that the cellular profiles were similar at one week but the differences between males and females were similar to those of adults by four weeks of age.
To test whether hormonal signals do indeed underlie the differences, the researchers eliminated sex hormones—estrogen and testosterone—from cohorts of mice by gonadectomy. Interestingly, the cellular compositions of male and female hearts soon became similar: rapidly so, as the changes occurred over a two-week period. When the gonadectomized mice were treated with hormones—17-beta estradiol or testosterone propionate—for four weeks, however, the cellular changes were partially reversed, and differences between the sexes became apparent again. The results indicate that the hormones are essential for regulating the differences in cardiac cellular composition.
The study provides a foundation for further investigation into the influence of biological sex on cardiac cellular makeup and how it can affect cardiovascular function and disease. In addition, it will be important to more fully explore the cellular composition of human hearts. But given that much research into cardiac function and therapeutic development has been done only in males to date, the findings underline the importance of incorporating sex differences into future preclinical and clinical cardiovascular research.