Recombinant human relaxin reduces hypoxic pulmonary hypertension in the rat

The fibroproliferative changes in pulmonary artery (PA) remodeling are partially prevented by antifibrotic agents. Relaxin (RIx), a hormone involved in loosening collagen bundles in ligaments during parturition, has antifibrotic and vasodilator properties that may prevent pulmonary vascular remodeling. In the hypoxia model of pulmonary hypertension, two doses of recombinant human relaxin (rhRIx 24 [high] or 5 [low] mg X 10(-2)/kg d(-1)) were administered subcutaneously continuously for 10 d to hypoxic (10 % O-2) rats. At day 11, right ventricular pressure (Pa X 10(2)) was reduced by rhRIx in a dose-dependent manner (15 +/- 1* control; 28 +/- 1 hypoxia; 23 +/- 1* low; 20 +/- 1* high; n = 10-14/group, *P < 0.05 vs. hypoxia). High rhRIx ameliorated increased collagen accumulation (mu g hydroxyproline/vessel) in main PAs (87 +/- 6) vs. untreated hypoxia (102 +/- 2) (n=5/group, P < 0.05). Infusion of rhRIx had no effect on air-breathing rats, and acute administration did not alter blood pressure in hypoxic rats. Fibroblasts cultured from rat PAs spontaneously expressed collagen and fibronectin, and treatment with TGF-beta increased secretion 26- and 25 X 10(-1)-fold, respectively. Addition of rhRIx to transforming growth factor-beta-stimulated fibroblasts inhibited collagen (37 %) and fibronectin (38 %) secretion vs. vehicle (n = 4 per group, both P < 0.05). We conclude that rhRlx inhibits the early fibroproliferative response in hypoxic pulmonary hypertension and the mechanism may be due in part to suppression of collagen synthesis. (c) 2005 Elsevier Ltd. All rights reserved.