Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension

Am J Physiol Heart Circ Physiol. 2014 Aug 1;307(3):H273-83. doi: 10.1152/ajpheart.00758.2013. Epub 2014 Jun 6.

Abstract

Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction and failure. Paradoxically, women are more frequently diagnosed with PAH but have better RV systolic function and survival rates than men. The mechanisms by which sex differences alter PAH outcomes remain unknown. Here, we sought to study the role of estrogen in RV functional remodeling in response to PAH. The SU5416-hypoxia (SuHx) mouse model of PAH was used. To study the role of estrogen, female mice were ovariectomized and then treated with estrogen or placebo. SuHx significantly increased RV afterload and resulted in RV hypertrophy. Estrogen treatment attenuated the increase in RV afterload compared with the untreated group (effective arterial elastance: 2.3 ± 0.1 mmHg/μl vs. 3.2 ± 0.3 mmHg/μl), and this was linked to preserved pulmonary arterial compliance (compliance: 0.013 ± 0.001 mm(2)/mmHg vs. 0.010 ± 0.001 mm(2)/mmHg; P < 0.05) and decreased distal muscularization. Despite lower RV afterload in the estrogen-treated SuHx group, RV contractility increased to a similar level as the placebo-treated SuHx group, suggesting an inotropic effect of estrogen on RV myocardium. Consequently, when compared with the placebo-treated SuHx group, estrogen improved RV ejection fraction and cardiac output (ejection fraction: 57 ± 2% vs. 44 ± 2% and cardiac output: 9.7 ± 0.4 ml/min vs. 7.6 ± 0.6 ml/min; P < 0.05). Our study demonstrates for the first time that estrogen protects RV function in the SuHx model of PAH in mice directly by stimulating RV contractility and indirectly by protecting against pulmonary vascular remodeling. These results underscore the therapeutic potential of estrogen in PAH.

Keywords: cardiopulmonary hemodynamics; estrogen; pulmonary artery hypertension; rv catheterization; sex difference.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterial Pressure / drug effects
  • Cardiotonic Agents / administration & dosage*
  • Compliance
  • Disease Models, Animal
  • Drug Implants
  • Estradiol / administration & dosage*
  • Estrogen Replacement Therapy*
  • Estrogens / administration & dosage*
  • Female
  • Heart Ventricles / drug effects*
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Hypertension, Pulmonary / diagnosis
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / complications
  • Indoles
  • Mice, Inbred C57BL
  • Myocardial Contraction / drug effects
  • Ovariectomy
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Pyrroles
  • Stroke Volume / drug effects
  • Time Factors
  • Vascular Remodeling / drug effects
  • Ventricular Dysfunction, Right / diagnosis
  • Ventricular Dysfunction, Right / etiology
  • Ventricular Dysfunction, Right / physiopathology
  • Ventricular Dysfunction, Right / prevention & control*
  • Ventricular Function, Right / drug effects*

Substances

  • Cardiotonic Agents
  • Drug Implants
  • Estrogens
  • Indoles
  • Pyrroles
  • Estradiol
  • Semaxinib