Swimming and Electrical Muscle Stimulation Attenuate Early Pulmonary Vascular Remodeling Without Restoring Circulating Irisin in Monocrotaline-Induced Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease with limited therapeutic options. Exercise exerts beneficial cardiovascular effects partly through myokines such as irisin. This study investigated the preventive/early-intervention effects of swimming and electrical muscle stimulation (EMS) in a monocrotaline (MCT)-induced rat model of PAH and evaluated whether circulating irisin and its putative receptor, integrin αV/β5, are associated with these effects. PAH was induced in Wistar rats by a single intraperitoneal injection of MCT (60 mg/kg). Swimming and EMS were applied for 4 weeks (30 min/day, 5 days/week). Right ventricular pressures, Fulton index, pulmonary vascular remodeling, integrin αV/β5 expression, serum irisin concentrations, and pulmonary artery vasoreactivity were evaluated. MCT significantly increased mean and diastolic right ventricular pressures, Fulton index, medial wall thickness, and vascular occlusion, consistent with early pulmonary vascular remodeling. Acetylcholine-induced vasodilation was impaired, whereas responses to exogenous irisin were unchanged. Both swimming and EMS attenuated vascular remodeling, improved endothelial function and irisin-mediated vasodilation, and reduced αV/β5 expression. Blockade of αV/β5 with cilengitide did not modify irisin-induced vascular responses. Serum irisin concentrations were reduced in PAH and were not restored by either intervention. Swimming and EMS attenuated early pulmonary vascular remodeling and improved endothelial function in this early-intervention model. Although circulating irisin concentrations remained reduced and αV/β5 blockade did not alter vascular responses, the present findings do not support a major mechanistic role for circulating irisin or αV/β5-mediated signaling. Further studies are needed to clarify the tissue-specific mechanisms underlying these protective effects.