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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:841.)
© 2008 American Heart Association, Inc.

Integrated Physiology/Experimental Medicine

Prokineticin Receptor-1 Induces Neovascularization and Epicardial-Derived Progenitor Cell Differentiation

Kyoji Urayama; Célia Guilini; Gulen Turkeri; Selcuk Takir; Hitoshi Kurose; Nadia Messaddeq; Andrée Dierich; Canan G. Nebigil

From the Centre National de la Recherche Scientifique (CNRS) (K.U., C.G., G.T., S.T., C.G.N.), Université Louis Pasteur-Strasbourg I, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France; the Department of Pharmacology and Toxicology (H.K.), Kyushu University, Fukuoka, Japan; and Institut de Génétique et de Biologie Moléculaire et Cellulaire (N.M., A.D.), Inserm, U 596, CNRS, Illkirch, France.

Correspondence to Canan G. Nebigil, CNRS/ULP, UMR 7175, ESBS, Bld. Sébastien Brandt BP. 10413, F-67412 Illkirch, France. E-mail nebigil{at}esbs.u-strasbg.fr

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.

Methods and 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.

Conclusion— 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.

Prokineticins are secreted bioactive proteins that bind to 2 GPCRs, PKR1 and PKR2. Using transgenic mice, coculture cell models, EPDC, and PKR1-null mutants, we showed that cardiomyocyte-PKR1 signaling upregulates its own ligand prokineticin-2 as a paracrine factor, trigerring pluripotency of EPDCs, to promote neovascularization.

Key Words: GPCR • angiogenesis • transgenic mice • differentiation • prokineticin

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The Adult Epicardium: Realizing the Potential for Neovascular Therapy

Paul R. Riley
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