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Title: Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells.
Authors: Favre, Shirley
Gambini, Elisa
Nigro, Patrizia
Scopece, Alessandro
Bianciardi, Paola
Caretti, Anna
Pompilio, Giulio
Corno, Antonio F.
Vassalli, Giuseppe
von Segesser, Ludwig K.
Samaja, Michele
Milano, Giuseppina
First Published: 18-Nov-2016
Publisher: Wiley Open Access for Foundation for Cellular and Molecular Medicine
Citation: Journal of Cellular and Molecular Medicine, 2017, 21 (5), pp. 871-880
Abstract: 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.
DOI Link: 10.1111/jcmm.13026
ISSN: 1582-1838
eISSN: 1582-4934
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: 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.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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