Activation of a Novel Estrogen Receptor Ameliorates Experimental Pulmonary Hypertension in Male Rats

Introduction: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling that leads to uncompensated RV failure, and premature death. Preclinical studies have demonstrated that activation of the G protein-coupled estrogen receptor (GPER) is cardioprotective in male rats, and that a selective agonist G1, elicits vascular relaxation in rats of either sex. This work investigated the effects of G1 in male rats with monocrotaline (MCT)-induced PAH. Methods and Results: Male Wistar rats received a single intraperitoneal injection of MCT (60 mg/kg) for PAH induction. Experimental groups were: control, MCT + vehicle, and MCT + G1 (400 μg/kg/day s.c.). Animals were treated with vehicle or G1 for 14 days after the onset of disease (n = 5 per group). Treadmill test and transthoracic echocardiography were performed to access exercise capacity and cardiac function, respectively. RV systolic pressure (RVSP) and mean arterial pressure (MAP) were measured. Time to exhaustion in the treadmill (s) was reduced from 1042.0 ± 66.4 to 188.0 ± 53.1 (MCT + vehicle) and recovered to 809.4 ± 61.5 after G1 treatment. Pulmonary acceleration time (PAT) (ms) was reduced from 44.7 ± 1.4 to 24.7 ± 1.2 in MCT + vehicle group and restored to 41.8 ± 1.0 in MCT + G1 group. RVSP (mmHg) was increased from 24.6 ± 0.6 to 41.1 ± 1.4 (MCT + vehicle) and was reduced to 27.5 ± 0.7 (MCT + G1). MAP (mmHg) was reduced from 100.9 ± 1.1 to 77.1 ± 2.4 (MCT + vehicle), indicating HF induced by the RV dysfunction, and G1 normalized it to 92.4 ± 1.4. G1 decreased pulmonary vascular remodeling and normalized endothelial nitric oxide enzyme levels in lungs from PAH rats. PLB/SERCA2a ratio increased, as a sign of contractility dysfunction, in PAH rats and tumor necrosis factor alpha upregulation was significantly correlated with these Ca 2+ handling proteins impairment. Activation of GPER beneficially reduced PLB/SERCA2a ratio and TNF-α levels in RV tissue of MCT-induced PAH rats. Conclusions: G1 was effective to reverse PAH-induced RV dysfunction and exercise intolerance in male rats, a finding that may have important implications for ongoing clinical evaluation of new drugs for the treatment of the disease.