ORIGINAL RESEARCH published: 06 December 2018 doi: 10.3389/fphar.2018.01395 Edited by: Chrishan S. Samuel, Monash University, Australia Reviewed by: Bin-Nan Wu, Kaohsiung Medical University, Taiwan Brad Randal Scott Broughton, Monash University, Australia *Correspondence: Gisele Zapata-Sudo gzsudo@oi.com.br Specialty section: This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology Received: 01 February 2018 Accepted: 12 November 2018 Published: 06 December 2018 Citation: Alencar AKN, Pimentel-Coelho PM, Montes GC, da Silva MdMC, Mendes LVP, Montagnoli TL, Silva AMS, Vasques JF, Rosado-de-Castro PH, Gutfilen B, Cunha VdMN, Fraga AGM, Silva PMRe, Martins MA, Ferreira TPT, Mendes-Otero R, Trachez MM, Sudo RT and Zapata-Sudo G (2018) Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice. Front. Pharmacol. 9:1395. doi: 10.3389/fphar.2018.01395 Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice Allan K. N. Alencar 1 , Pedro M. Pimentel-Coelho 2 , Guilherme C. Montes 1 , Marina de M. C. da Silva 1 , Luiza V. P. Mendes 1 , Tadeu L. Montagnoli 1 , Ananssa M. S. Silva 1 , Juliana Ferreira Vasques 2 , Paulo Henrique Rosado-de-Castro 3 , Bianca Gutfilen 4 , Valéria do M. N. Cunha 1 , Aline G. M. Fraga 5 , Patrícia M R e Silva 6 , Marco Aurélio Martins 6 , Tatiana Paula Teixeira Ferreira 6 , Rosalia Mendes-Otero 2 , Margarete M. Trachez 1 , Roberto T. Sudo 1 and Gisele Zapata-Sudo 1 * 1 Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 2 Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 3 Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 4 Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 5 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Rio de Janeiro, Brazil, 6 Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil 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 × 10 5 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. Keywords: pulmonary arterial hypertension, cell proliferation, inflammation, apoptosis, human mesenchymal stem cell Frontiers in Pharmacology | www.frontiersin.org 1 December 2018 | Volume 9 | Article 1395