P22 Cardio-pulmonary and body-weight effects of estriol

Rationale Female sex is a risk factor for the development of pulmonary arterial hypertension (PAH) but once affected, women present a better response to treatment and longer survival as compared to men. We recently observed elevated plasma levels of estriol (E3 or 16α-hydroxyestradiol) in female idiopathic PAH patients and in male and female patients with portoPAH. E3 is produced during pregnancy and has the weakest binding affinity to estrogen receptors a and b of the three major estrogens (estriol, E1 and 17b-estradiol, E2). Currently, one-third of PAH patients are obese and in postmenopausal women and in men, estrogen is produced in extragonadal tissues including adipose tissue where it acts in a paracrine fashion and is secreted into the circulation. Herein we investigated the role of obesity and E3 in adult cardio/pulmonary-vascular system. Methods Male and female mice bearing knock-in of human bone morphogenetic protein receptor 2 (BMPR2) R899X mutation were fed high fat diet for 24 weeks and injected with 1.5 mg/kg/day of E3 intraperitoneally for 14 days. Hemodynamic profile was determined by pressure-volume loop catheterization under terminal anesthesia. Wild type littermates served as controls. Gene expression in harvested lung tissues was assessed by qRT-PCR. Results Administration of E3 significantly decreased the weight of white adipose tissue in both male and female obese wild type as well as BMPR2 deficient mice. E3 had no effect on right ventricle systolic pressure (RVSP) of wild type male and female obese mice treated with E3. Obese male mice with BMPR2 deficiency and E3 treatment exhibited decrease in RVSP. Pro-fibrotic gene expression was decreased in the lungs of mice treated with E3. Conclusions Administration of E3 significantly decreased white adipose tissue mass in obese male and female mice. Additionally, markers of fibrosis were also reduced in the lungs of obese mice treated with E3.