title: Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation.
abstract: OBJECTIVE
  Identification of novel factors that contribute to myocardial repair and collateral vessel growth hold promise for treatment of heart diseases. We have shown that transient prokineticin receptor-1 (PKR1) gene transfer protects the heart against myocardial infarction in a mouse model. Here, we investigated the role of excessive PKR1 signaling in heart.
  
  
  RESULTS
  Transgenic mice overexpressing PKR1 in cardiomyocytes displayed no spontaneous abnormalities in cardiomyocytes but showed an increased number of epicardial-derived progenitor cells (EPDCs), capillary density, and coronary arterioles. Coculturing EPDCs with H9c2 cardiomyoblasts overexpressing PKR1 promotes EPDC differentiation into endothelial and smooth muscle cells, mimicking our transgenic model. Overexpressing PKR1 in H9c2 cardiomyoblasts or in transgenic hearts upregulated prokineticin-2 levels. Exogenous prokineticin-2 induces significant outgrowth from neonatal and adult epicardial explants, promoting EPDC differentiation. These prokineticin-2 effects were abolished in cardiac explants from mice with PKR1-null mutation. Reduced capillary density and prokineticin-2 levels in PKR1-null mutant hearts supports the hypothesis of an autocrine/paracrine loop between PKR1 and prokineticin-2.
  
  
  CONCLUSIONS
  Cardiomyocyte-PKR1 signaling upregulates its own ligand prokineticin-2 that acts as a paracrine factor, triggering EPDCs proliferation/differentiation. This study provides a novel insight for possible therapeutic strategies aiming at restoring pluripotency of adult EPDCs to promote neovasculogenesis by induction of cardiomyocyte PKR1 signaling.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur-Strasbourg I, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Urayama
authors.forename: Célia
authors.initials: C
authors.lastname: Guilini
authors.forename: Gulen
authors.initials: G
authors.lastname: Turkeri
authors.forename: Selcuk
authors.initials: S
authors.lastname: Takir
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Andrée
authors.initials: A
authors.lastname: Dierich
authors.forename: Canan G
authors.initials: CG
authors.lastname: Nebigil
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010496:Pericardium / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse; C061570:protein kinase N; D011493:Protein Kinase C