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|Title:||Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells.|
Corno, Antonio F.
von Segesser, Ludwig K.
|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.|
|Rights:||Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), 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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