Am J Physiol Regul Integr Comp Physiol. 2026 May 14. doi: 10.1152/ajpregu.00040.2026. Online ahead of print.
ABSTRACT
Sex is increasingly recognized as a critical biological variable in preclinical cardiovascular research yet baseline physiological differences between male and female animals-and the experimental decisions that shape their interpretation-remain incompletely defined. Here, we establish a quantitative experimental framework by systematically characterizing growth trajectories, cardiac scaling, anesthetic sensitivity, estrous-cycle effects, and myocardial mechanics in male, ovary-intact female, and ovariectomized (OVX) female Sprague-Dawley rats. Marked sex- and hormone-dependent differences in body growth rendered simultaneous age- and weight-matching impractical and led to distinct - and sometimes opposing - inferences regarding normalized cardiac mass depending on cohort standardization strategy. Baseline hemodynamics were comparable across sex and estrous stage, whereas ovarian hormone status modulated right ventricular structure and passive myocardial mechanics. Physiological fluctuations in estrogen were associated with estrogen-dependent changes in right ventricular mass, thickness, and compliance, while early ovariectomy produced persistent increases in myocardial stiffness independent of hemodynamic load. OVX females also exhibited heightened sensitivity to isoflurane during surgical procedures, particularly during early operative phases. Together, these findings demonstrate that sex, circulating estrogen, and timing of ovarian hormone loss shape baseline cardiovascular phenotypes. Rather than treating sex-related variability as experimental noise, this study provides practical guidance for experimental design, normalization, and interpretation in preclinical cardiovascular research.
PMID:42133341 | DOI:10.1152/ajpregu.00040.2026