Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells.pdf (1004.42 kB)
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Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells.

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journal contribution
posted on 27.11.2017, 12:15 by Shirley Favre, Elisa Gambini, Patrizia Nigro, Alessandro Scopece, Paola Bianciardi, Anna Caretti, Giulio Pompilio, Antonio F. Corno, Giuseppe Vassalli, Ludwig K. von Segesser, Michele Samaja, Giuseppina Milano
The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit(+) cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c-kit(+) cells that colocalize with tyrosine kinase receptor 2 (VEGF-R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia-induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia-inducible factor (HIF)-1α. Furthermore, sildenafil depressed the number of CXCR4(+) cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM-derived c-kit(+) cells in the pulmonary tissue. The attenuation of the recruitment of BM-derived c-kit(+) cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling.

Funding

This work was supported by the Swiss Heart Foundation.

History

Citation

Journal of Cellular and Molecular Medicine, 2017, 21 (5), pp. 871-880

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Journal of Cellular and Molecular Medicine

Publisher

Wiley Open Access for Foundation for Cellular and Molecular Medicine

issn

1582-1838

eissn

1582-4934

Acceptance date

26/09/2016

Copyright date

2016

Available date

27/11/2017

Publisher version

http://onlinelibrary.wiley.com/doi/10.1111/jcmm.13026/abstract

Notes

Additional Supporting Information may be found online in thesupporting information tab for this article:Figure S1Representative histogram plot for c-kit marker in wholeblood measured by FACS (left panel); right panel indicates the quan-tification of circulating c-kit+cells. Same details as in the manuscript.Figure S2FACS analysis for CXCR4 marker in WB cells: leftpanel shows a representative histogram plot, the right panelindicates the quantification of circulating CXCR4+cells. Samedetails as in the manuscript.

Language

en