Introduction: Pulmonary arterial hypertension (PAH) results from pathological remodeling of the pulmonary vasculature. Apelin is a ligand of the G protein-coupled apelin receptor, a vasodilator and positive cardiac inotrope. Apelin expression is reduced in PAH. Administration of endogenous apelin peptide attenuated the increase in right ventricular systolic pressure (RVSP) and right ventricular (RV) hypertrophy but did not abolish vascular remodeling in monocrotaline (MCT)-exposed rats. We have demonstrated that MM07, a synthetic G protein-biased apelin receptor agonist, was more stable than apelin peptide and attenuated the increase in RVSP and RV hypertrophy in the MCT model. The effect of MM07 on the pulmonary vascular morphometry is not known.
Hypothesis: We hypothesised that MM07 would attenuate pulmonary vascular remodeling in MCT-exposed rats.
Methods: Male Sprague Dawley rats (187±2g) were randomly assigned to receive MCT (60mg/kg body weight) or saline subcutaneously on day 0. Animals in both groups were given daily intraperitoneal injections of either MM07 (1mg/kg body weight) or saline for 20 days. The lungs were extracted on day 21 and vascular remodeling was quantified as muscularization of small pulmonary vessels using smooth muscle actin staining and medial thickness in arterioles using elastic van Giesen staining. Group data were compared using one-way ANOVA with Tukey’s post-test.
Results: Compared to saline controls, the MCT group showed a higher proportion of fully muscularized vessels (14±1%, n=4 vs 32±1%, n=5, p≤0.001) and increased vessel wall thickness relative to diameter (10±1% vs 21±1%, p≤0.001). Compared to the MCT group both parameters were significantly reduced in MCT-injected rats treated with MM07 (fully muscularized vessels 24±2% p≤0.01; wall thickness 16±1%, p≤0.001, n=6). MM07 alone (n=4) did not alter vessel muscularization (15±1%, p≥0.05) or wall thickness (10±1%, p≥0.05) in control animals.
Conclusions: MM07 is the first biased apelin receptor agonist given to a disease model. In this proof of principle study, MM07 significantly attenuated pulmonary vascular remodelling, which is vital to preventing the development of PAH. In this aspect MM07 was better than previously reported for endogenous apelin peptide.