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.

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

“…The marginal increase in the proliferation of SMCs on exposure to EVs from monotreatment group macrophages was in accordance with our previous in vitro as well as in vivo published findings where we demonstrated that a “dual hit” of HIV and cocaine significantly exacerbates smooth muscle hyperplasia and PAH phenotype compared to a “single hit” of either cocaine or viral proteins (9, 12). In recent years, the role of EVs in intercellular communication has been well established (53) in the pathogenesis of various diseases, including pulmonary hypertension (54, 55). Plasma exosomes from mice with monocrotaline-induced PAH were demonstrated to cause pulmonary hypertension in healthy mice and this effect was reversed by administering exosomes derived from mesenchymal stem cells (23).…”

Exosomes from mesenchymal stem cells expressing miR‐125b inhibit neointimal hyperplasia via myosin IE

“…Extracellular vesicles derived from adipose MSCs have been shown to limit neointimal hyperplasia and in a study by Liu et al (2015) this was attributed to decreased macrophage infiltration, reduced expression of inflammatory cytokines and downregulation of the MAPK and PI3K signalling pathways. In another study, exosomes derived from pulmonary artery endothelial cells were shown to induce high levels of proliferation and exert anti‐apoptotic effects in pulmonary artery smooth muscle cells, contributing to vascular remodelling and the pathogenesis of pulmonary hypertension …”

“…In another study, exosomes derived from pulmonary artery endothelial cells were shown to induce high levels of proliferation and exert anti-apoptotic effects in pulmonary artery smooth muscle cells, contributing to vascular remodelling and the pathogenesis of pulmonary hypertension. 45 Accumulating evidence suggests that exosome-derived miRNAs may be involved in the regulation of various aspects of neointima formation via the modulation of target cell functions (eg proliferation and migration of VSMCs) and the resulting effects on vasculature homeostasis. 39,[46][47][48] It has been reported that MSC engraftment reduces vascular remodelling after coronary vessel balloon injury, this was demonstrated by a lower I/M, neointimal area and positive expression of PCNA in addition to enhanced re-endothelialisation after MSC transplantation.…”

Endothelial Extracellular Vesicles—Promises and Challenges

“…Hence, exosomes have gained interest as a source of biomarkers to assess the physiological condition of their cell of origin (de Jong et al, 2012). Both hypoxia and LPS have furthermore been shown to increase the release of exosomes from pulmonary artery ECs, which were involved in enhanced proliferation and resistance to apoptosis in pulmonary artery smooth muscle cells (Zhao et al, 2017). Additionally, ECs stimulated with transforming growth factor (TGF)-β1 induced shedding of VEGFR2-containing exosomes, which seemed to limit the effects of angiogenic stimuli on vascular sprouting (Jarad et al, 2017).…”