Exosomes Derived from Human Pulmonary Artery Endothelial Cells Shift the Balance between Proliferation and Apoptosis of Smooth Muscle Cells

Abstract

Background: The overproliferation of pulmonary vascular cells is noted in pulmonary hypertension. The role of exosomes from pulmonary artery endothelial cells (PAEC) in the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMC) remains unclear. Methods: Exosomes were isolated and purified from the culture medium of PAEC using a commercial kit. Lipopolysaccharide (LPS), hypoxia, and hydrogen peroxide were utilized to induce PAEC injury. Coculture of PAEC and PASMC was conducted using Transwell plates, and GW4869 was applied to inhibit exosome release. The proliferation and apoptosis level of PASMC was assayed by MTT assay, apoptosis staining, and cleaved caspase-3 immunoblotting. Plasma exosomes were isolated by differential ultracentrifugation. Results: LPS or hypoxia enhance exosome release from PAEC. Release of PAEC-derived exosomes positively correlates with LPS concentration. The coculture of LPS-disposed PAEC with PASMC leads to overproliferation and apoptosis resistance in PASMC, and the exosome inhibitor GW4869 can partly cancel out this effect. Exosomes derived from PAEC could be internalized into PASMC, and thus promote proliferation and induce apoptosis resistance in PASMC. Idiopathic pulmonary arterial hypertension patients exhibit a higher circulation level of endothelium-derived exosomes. Conclusions: Inflammation and hypoxia could induce PAEC to release exosomes. PAEC- derived exosomes are involved in overproliferation and apoptosis resistance in PASMC, by which they may contribute to the pathogenesis of pulmonary hypertension.