Mesenchymal stem cell–derived microvesicles alleviate pulmonary arterial hypertension by regulating renin-angiotensin system

Abstract

In recent years, microvesicles (MVs) derived from mesenchymal stem cells (MSCs) have been proved to be able to improve the outcome of pulmonary arterial hypertension (PAH) in many respects, but the underlying mechanisms of it still remain unclear. Because the renin-angiotensin system (RAS) has been found to be closely related to PAH, the present study was designed to investigate whether the effect of MSC-derived MVs on PAH was correlated with RAS. MVs were isolated and purified from bone marrow MSCs. PAH rat models were established by a single intraperitoneal injection of 1% monocrotaline (MCT, 50 mg/Kg). In vivo study, after 3 weeks of MCT exposure, Nor group and PAH group were injected with 0.5 mL saline every 2 days through tail vein, whereas MVs group was injected with 0.5 mL saline containing 30μg MVs and A-779 + MVs group injected with 0.5 mL saline containing 120μg A-779 and 30μg MVs until 5 weeks of MCT exposure. Whereafter all the groups were analyzed for hemodynamic evaluation, right ventricular hypertrophy index, pulmonary vessel wall thickness index and pulmonary vessel lumen area index, the inflammation score, the collagen fiber volume fraction, the levels of Ang-(1-7) and Ang-Ⅱin plasma and lung tissue, and the mRNA levels of ACE2 and ACE in the lung tissue. MVs derived from MSCs relieved the pulmonary artery pressure, right ventricular hypertrophy index, pulmonary vessel wall thickness index, pulmonary vessel lumen area index, the inflammation score, and the collagen fiber volume fraction. Moreover, in MVs group, ACE2 mRNA in the lung tissues and plasma levels of Ang-(1-7) were both upregulated compared with PAH group. On the contrary, ACE and Ang-II were decreased compared with PAH group. However, the enhanced protective effects observed in MVs group were diminished by the use of A-779, an inhibitor of Mas receptor in ACE2-Ang-(1-7)-Mas axis. MVs derived from bone marrow MSCs can exert beneficial effects against MCT-induced PAH in vivo, meanwhile shifting the balance from ACE-Ang-II-AT1R axis toward the ACE2-Ang-(1–7)-Mas axis, which might be one of the possible therapeutic mechanisms for MVs subcellular treatment.