Abstract
Aims: Pulmonary arterial hypertension (PAH) is a disease characterized by an increase in pulmonary vascular resistance and right ventricular (RV) failure. We aimed to determine the effects of human mesenchymal stem cell (hMSC) therapy in a SU5416/hypoxia (SuH) mice model of PAH.Methods and Results: C57BL/6 mice (20–25 g) were exposure to 4 weeks of hypoxia combined vascular endothelial growth factor receptor antagonism (20 mg/kg SU5416; weekly s.c. injections; PAH mice). Control mice were housed in room air. Following 2 weeks of SuH exposure, we injected 5 × 105 hMSCs cells suspended in 50 μL of vehicle (0.6 U/mL DNaseI in PBS) through intravenous injection in the caudal vein. PAH mice were treated only with vehicle. Ratio between pulmonary artery acceleration time and RV ejection time (PAAT/RVET), measure by echocardiography, was significantly reduced in the PAH mice, compared with controls, and therapy with hMSCs normalized this. Significant muscularization of the PA was observed in the PAH mice and hMSC reduced the number of fully muscularized vessels. RV free wall thickness was higher in PAH animals than in the controls, and a single injection of hMSCs reversed RV hypertrophy. Levels of markers of exacerbated apoptosis, tissue inflammation and damage, cell proliferation and oxidative stress were significantly greater in both lungs and RV tissues from PAH group, compared to controls. hMSC injection in PAH animals normalized the expression of these molecules which are involved with PAH and RV dysfunction development and the state of chronicity.Conclusion: These results indicate that hMSCs therapy represents a novel strategy for the treatment of PAH in the future.
Highlights
Pulmonary arterial hypertension (PAH) is characterized by increased precapillary pressure as a consequence of exacerbated pulmonary artery (PA) wall remodeling and hypertrophy (Gnecchi et al, 2016)
Significant muscularization of the PA was observed in the PAH mice and human mesenchymal stem cell (hMSC) reduced the number of fully muscularized vessels
right ventricle (RV) free wall thickness was higher in PAH animals than in the controls, and a single injection of hMSCs reversed RV hypertrophy
Summary
Pulmonary arterial hypertension (PAH) is characterized by increased precapillary pressure as a consequence of exacerbated pulmonary artery (PA) wall remodeling and hypertrophy (Gnecchi et al, 2016) These are the main causes for the development of right ventricle (RV) dysfunction, subsequent irreversible RV failure, and sudden cardiac death in patients with PAH. In advanced stages of PAH, the obliteration of the vascular lumen due to excessive cell proliferation is accompanied by excessive vasoconstriction, chronically increasing the RV overload, a cardiac chamber that initiates one compensatory adaption. These pathophysiological events are followed by progressive RV enlargement, leading to heart failure. Favorable actions in the RV are required for better outcomes; there is a current search for pleiotropic interventional approaches with beneficial roles throughout the cardiopulmonary system (pulmonary vessel and cardiac cells)
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