Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats

Marina De Moraes Carvalho Da Silva,Grazielle Fernandes Da Silva,Rosália Mendez-Otero,Tadeu Lima Montagnoli,Allan Kardec Nogueira De Alencar,Juliana F Vasques,Pedro Moreno Pimentel-Coelho,Margarete Manhães Trahez,Roberto Takashi Sudo,Guilherme Carneiro Montes,Jaqueline Soares Da Silva,Gisele Zapata-Sudo,Bruna De Souza Rocha

doi:10.3390/cells9092120

Marina De Moraes Carvalho Da Silva, Grazielle Fernandes Da Silva + Show 11 more

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https://doi.org/10.3390/cells9092120

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Journal: Cells	Publication Date: Sep 18, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: Universidade Federal do Rio de Janeiro

Abstract

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.

Highlights

Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary artery (PA) wall remodeling and hypertrophy [1], while promoting inflammation [2] and vascular tonus dysfunction [3], Cells 2020, 9, 2120; doi:10.3390/cells9092120 www.mdpi.com/journal/cellsCells 2020, 9, 2120 which result in an increase in pulmonary arterial pressure [4]
24.0 ± 3.1 mmHg (Figure 2B), while PAH induced its increase to 52.1 ± 8.8 (SuHx + vehicle) mm
Increased RV systolic pressure (RVSP) was reduced by lodenafil and human umbilical cord mesenchymal stem cells (hMSCs) to 37.8 ± 3.5 and 30.8 ± 3.2 mmHg, respectively

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary artery (PA) wall remodeling and hypertrophy [1], while promoting inflammation [2] and vascular tonus dysfunction [3], Cells 2020, 9, 2120; doi:10.3390/cells9092120 www.mdpi.com/journal/cellsCells 2020, 9, 2120 which result in an increase in pulmonary arterial pressure [4]. Drug classes currently approved for PAH treatment focus on promoting pulmonary artery relaxation [6], reducing RV overload and improving quality of life [7]. (PDE5) inhibitors approved to treat PAH are sildenafil, tadalafil and vardenafil [7], whose mechanism involves increasing the bioavailability of cyclic guanosine monophosphate (cGMP) by inhibiting its degradation [8]. Mortality consequent to PAH is high [12] because current therapy fails to reverse the structural and signaling changes in pulmonary arteries (deregulated angiogenesis, high production and release of growth factors, strong resistance to apoptosis, abnormal formation of an inflammatory environment within and surrounding vessel walls) [13] and the RV (ischemia, metabolic dysfunction, fibrosis) [5]. PAH treatment should ideally consider the prevention or reversion of these alterations [14]

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