title: Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells.
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.
authors.affiliation: Laboratory of Cardiovascular Research, Department of Surgery and Anesthesiology, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Shirley
authors.initials: S
authors.lastname: Favre
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gambini
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nigro
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Scopece
authors.affiliation: Department of Health Science, University of Milan, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bianciardi
authors.affiliation: Department of Health Science, University of Milan, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caretti
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
authors.affiliation: Glenfield Hospital, Leicester, UK.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Corno
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Lausanne, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vassalli
authors.affiliation: Laboratory of Cardiovascular Research, Department of Surgery and Anesthesiology, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Ludwig K
authors.initials: LK
authors.lastname: von Segesser
authors.affiliation: Department of Health Science, University of Milan, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Samaja
authors.affiliation: Laboratory of Cardiovascular Research, Department of Surgery and Anesthesiology, University Hospital Lausanne, Lausanne, Switzerland.|Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Milano
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000473:pathology*; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D019718:Receptors, CXCR4; D000068677:Sildenafil Citrate; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D006152:Cyclic GMP
keywords: CXCR4 receptor; bone marrow progenitor cells; c-kit cells; chronic hypoxia; pulmonary hypertension; sildenafil