Strategies and methods to study sex differences in cardiovascular structure and function: a guide for basic scientists

Abstract

BackgroundCardiovascular disease remains the primary cause of death worldwide. In the US, deaths due to cardiovascular disease for women exceed those of men. While cultural and psychosocial factors such as education, economic status, marital status and access to healthcare contribute to sex differences in adverse outcomes, physiological and molecular bases of differences between women and men that contribute to development of cardiovascular disease and response to therapy remain underexplored.MethodsThis article describes concepts, methods and procedures to assist in the design of animal and tissue/cell based studies of sex differences in cardiovascular structure, function and models of disease.ResultsTo address knowledge gaps, study designs must incorporate appropriate experimental material including species/strain characteristics, sex and hormonal status. Determining whether a sex difference exists in a trait must take into account the reproductive status and history of the animal including those used for tissue (cell) harvest, such as the presence of gonadal steroids at the time of testing, during development or number of pregnancies. When selecting the type of experimental animal, additional consideration should be given to diet requirements (soy or plant based influencing consumption of phytoestrogen), lifespan, frequency of estrous cycle in females, and ability to investigate developmental or environmental components of disease modulation. Stress imposed by disruption of sleep/wake cycles, patterns of social interaction (or degree of social isolation), or handling may influence adrenal hormones that interact with pathways activated by the sex steroid hormones. Care must be given to selection of hormonal treatment and route of administration.ConclusionsAccounting for sex in the design and interpretation of studies including pharmacological effects of drugs is essential to increase the foundation of basic knowledge upon which to build translational approaches to prevent, diagnose and treat cardiovascular diseases in humans.

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

“…Other factors that should be considered include 1) the concentrations of testosterone (physiological, supraphysiological); 2) the steroid ester (testosterone cypionate, decanoate, undecanoate, enanthate, propionate, heptylate, caproate, phenylpropionate, isocaproate, acetate), which changes the compound solubility in water and slows the release of the parent steroid, used in the different studies; and 3) the "sex" of the cell/tissue where the effects of testosterone are being addressed. Although most signaling pathways are common in cells/tissues derived from females and males, some pathways may show sex differences or yet cells/tissues derived from females and males may differentially respond to sex hormones (41,42). The complexity of testosterone effects is evident, and further studies are required for a better understanding of the pro-or antioxidative/apoptotic effects of testosterone, especially in the cardiovascular system.…”

Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats

“…Moreover, there is a growing literature suggesting that estrogen in particular can mediate sex differences in cardiovascular function via both nuclear estrogen receptor (ER)-␣ and -␤ as well as via membrane-associated ERs including G protein-coupled estrogen receptor 1 (GPER) (1). The relative importance of these receptors and individual signal transduction pathways as the cellular basis for the cardiovascular sex differences to alcohol will require additional research using established approaches (54).…”

Conceptual frameworks and mouse models for studying sex differences in physiology and disease: Why compensation changes the game

“…One sex may be affected by a specific disease much more than the other (Karastergiou et al, 2012: Miller et al, 2011: Sandberg and Ji, 2012: Voskuhl, 2011), so that even a basic appreciation of disease mechanisms requires understanding how sex-biased factors influence the disease. The majority of basic science research is performed on males (Beery and Zucker, 2011), but conclusions drawn from those studies may not apply fully to females.…”