The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease

Abstract

Nearly one-third of deaths in the United States are caused by cardiovascular disease (CVD) each year. In the past, CVD was thought to mainly affect men, leading to the exclusion of women and female animals from clinical studies and preclinical research. In light of sexual dimorphisms in CVD, a need exists to examine baseline cardiac differences in humans and the animals used to model CVD. In humans, sex differences are apparent at every level of cardiovascular physiology from action potential duration and mitochondrial energetics to cardiac myocyte and whole-heart contractile function. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. Although endogenous estrogen is most likely a mediator of the observed functional differences in both health and disease, the signaling mechanisms involved are complex and are not yet fully understood. To investigate how sex modulates CVD development, animal models are essential tools and should be useful in the development of therapeutics. This review will focus on describing the cardiovascular sexual dimorphisms that exist both physiologically and in common animal models of CVD.

Keywords: cardiovascular diseases; estrogens; gonadal steroid hormones; heart failure; sex characteristics.

Figure 1

Cardiac action potential waveform in men (blue) and women (red). I_Na, sodium; I_CaL, L-type slow inward calcium current; I_Ks, slow delayed potassium rectifier; I_kr, rapid delayed potassium rectifier. Adapted from Zipes DP, et al., 2013.

Figure 2

Action potential waveform in (A) adult human and (B) mouse ventricular cardiac myocytes. Currents (I) contributing to each component of the action potential are shown below. I_Na, sodium current; I_CaL, L-type slow inward calcium current; I_tof, fast transient outward potassium current; Itos, slow transient outward potassium current; IKs, slow delayed potassium rectifier; IKr, rapid delayed potassium rectifier. Adapted from Nerbonne, J 2004.

Figure 3

Phosphorylation of RTKs in ARVMs isolated from males and females. A. Baseline phosphorylation levels of RTKs in female and male ARVMs. B. Phosphorylation levels of RTKs in female and male ARVMs treated with 300nmol/L estradiol, relative to vehicle treated. Red bars, female; blue bars, male. A: n = 2 pooled preparations, 2–3 rats per preparation. B: n = 3 pooled preparations, 1 rat per preparation.

Figure 4

Male and female rodent hearts adapt differently to pathological stimuli. While left ventricles of both sexes increase in size to response to increases in metabolic demand, male hearts are more likely to develop fibrosis, apoptosis and progress to heart failure. Heart image copyright ©2016 Abcam.