Abstract
BackgroundExperimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH.MethodsTwenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 105 adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial–mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68+ and CD163+ macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated.ResultsIn the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68+ macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial–mesenchymal transition.ConclusionIn MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype.
Highlights
Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH)
In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype
Echocardiography and hemodynamic measurements Fourteen days after MCT induction of PAH, the pulmonary artery acceleration time (PAT)/ pulmonary artery ejection time (PET) ratio was reduced in PAH animals compared to CTRL, suggesting pulmonary hypertension (0.38 ± 0.09 vs 0.47 ± 0.08 respectively; p = 0.016)
Summary
Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). These studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Specific features of the vascular remodeling seen in PAH include apoptosis and proliferation of pulmonary vascular endothelial cells, muscularization of distal pulmonary arterioles, deposition of extracellular matrix proteins, and perivascular inflammation [2]. Besides the role of inflammation, specific growth factors with proangiogenic effects may contribute to endothelial cell proliferation and fibroblast activation, which, in turn, contribute toward lung vascular remodeling [8, 10, 12]
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