AUTHOR=Alencar Allan K. N. , Pimentel-Coelho Pedro M. , Montes Guilherme C. , da Silva Marina de M. C. , Mendes Luiza V. P. , Montagnoli Tadeu L. , Silva Ananssa M. S. , Vasques Juliana Ferreira , Rosado-de-Castro Paulo Henrique , Gutfilen Bianca , Cunha Valéria do M. N. , Fraga Aline G. M. , Silva Patrícia M R e , Martins Marco Aurélio , Ferreira Tatiana Paula Teixeira , Mendes-Otero Rosalia , Trachez Margarete M. , Sudo Roberto T. , Zapata-Sudo Gisele 

TITLE=Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01395

DOI=10.3389/fphar.2018.01395

ISSN=1663-9812

ABSTRACT=<p><bold>Aims:</bold> 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.</p><p><bold>Methods and Results:</bold> 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 <italic>s.c.</italic> injections; PAH mice). Control mice were housed in room air. Following 2 weeks of SuH exposure, we injected 5 × 10<sup>5</sup> 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.</p><p><bold>Conclusion:</bold> These results indicate that hMSCs therapy represents a novel strategy for the treatment of PAH in the future.</p>