title: Phosphodiesterase-5 inhibitor tadalafil acts on endothelial progenitor cells by CXCR4 signalling.
abstract: It has been proposed that endothelial progenitor cells (EPC), originating from the bone marrow contribute to neo-angiogenesis in vivo by forming endothelial cells. Once released in the bloodstream, EPC home at the site of vascular damage where they participate in endothelium regeneration. In this process CXCR4 plays a key role. Recently we demonstrated that a prolonged therapy with phosphodiesterase-5 (PDE5) inhibitors does improve endothelial function and increases circulating EPC, suggesting a role of PDE5 in EPC physiology. Here we tested the expression of PDE5 and CXCR4 on cultured, circulating, and bone marrow resident EPC, and we studied the effect in vivo and in vitro of PDE5 inhibition after administration of a PDE5 inhibitor (tadalafil) on EPC, in term of CXCR4 expression. We documented that in vivo and in vitro EPC express both PDE5 and CXCR4, and that tadalafil administration induced a significant increase in EPC number and the relative CXCR4 expression. This effect is inhibited by selective CXCR4 antagonist. We thus demonstrated that PDE5 inhibition acts on CXCR4 signalling in EPC and we can suppose an involvement of cGMP second messenger system in both EPC release from the bone marrow and EPC-mediated peripheral re-endothelization.
authors.affiliation: Department of Histology, Microbiology and Medical Biotechnologies, Centre for Male Gamete Cryopreservation, University of Padova, Italy. carlo.foresta@unipd.it
authors.forename: Carlo
authors.initials: C
authors.lastname: Foresta
authors.forename: Luca
authors.initials: L
authors.lastname: De Toni
authors.forename: Sabina
authors.initials: S
authors.lastname: Magagna
authors.forename: Alessandro
authors.initials: A
authors.lastname: Galan
authors.forename: Andrea
authors.initials: A
authors.lastname: Garolla
mesh_terms: D000328:Adult; D001596:Benzylamines; D002243:Carbolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D000080027:Cyclams; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000068581:Tadalafil
chemical_list: D001596:Benzylamines; D002243:Carbolines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010726:Phosphodiesterase Inhibitors; D019718:Receptors, CXCR4; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C088327:plerixafor