Célia Guilini

Publications (3)17.88 Total impact

• Article: Transgenic myocardial overexpression of prokineticin receptor-2 (GPR73b) induces hypertrophy and capillary vessel leakage.

  Kyoji Urayama, Deniz B Dedeoglu, Célia Guilini, Stefan Frantz, Georg Ertl, Nadia Messaddeq, Canan G Nebigil
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  ABSTRACT: Prokineticins are small secreted bioactive molecules. They exert their biological activity by binding to two G protein-coupled receptors. Previously, we have shown that the overexpression of prokineticin receptor-1 (PKR1) in transgenic (TG) mouse hearts induced neovascularization. Since PKR1 and PKR2 are 85% identical and expressed in cardiovascular tissues, we hypothesized that PKR2 may also contribute to cardiomyocyte growth and vascularization. We have generated TG mice overexpressing PKR2 in cardiomyocytes. TG mice exhibit increased hypertrophic gene expression and heart-to-body weight ratio accompanied by an increased length of cardiomyocytes at the age of 12 weeks. Increased left ventricular end-systolic and diastolic diameters without cardiac dysfunction at the age of 24 weeks indicate that TG mice have an eccentric hypertrophy with compensated cardiac function. Quantitative morphological analysis showed that TG hearts have a normal microvessel density and number of branch points. However, they exhibit increased abnormal endothelial cell shape and ultrastructure, changed cellular distribution of a tight junction protein zona occludens-1 (ZO-1), and vascular leakage in heart without a rise of angiogenic factor levels at early and late age. The application of media conditioned by H9c2 cardioblast cells overexpressing PKR2 significantly induced impaired ZO-1 localization in H5V endothelial cells, mimicking the TG model. These findings provide the first genetic evidence that cardiomyocyte PKR2 signalling leads to eccentric hypertrophy in an autocrine regulation and impaired endothelial integrity in a paracrine regulation without inducing angiogenesis. These TG mice may provide a new genetic model for heart diseases.
  Cardiovascular research 10/2008; 81(1):28-37. · 5.80 Impact Factor
• Article: 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
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  ABSTRACT: 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. 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. 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.
  Arteriosclerosis Thrombosis and Vascular Biology 06/2008; 28(5):841-9. · 6.37 Impact Factor
• Article: The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis.

  Kyoji Urayama, Célia Guilini, Nadia Messaddeq, Kai Hu, Marja Steenman, Hitoshi Kurose, Georg Ert, Canan G Nebigil
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  ABSTRACT: Prokineticins are potent angiogenic factors that bind to two G protein-coupled receptors to initiate their biological effects. We hypothesize that prokineticin receptor-1 (PKR1/GPR73) signaling may contribute to cardiomyocyte survival or repair in myocardial infarction. Since we showed that prokineticin-2 and PKR1 are expressed in adult mouse heart and cardiac cells, we investigated the role of prokineticin-2 on capillary endothelial cell and cardiomyocyte function. In cultured cardiac endothelial cells, prokineticin-2 or overexpression of PKR1 induces vessel-like formation without increasing VEGF levels. In cardiomyocytes and H9c2 cells, prokineticin-2 or overexpressing PKR1 activates Akt to protect cardiomyocytes against oxidative stress. The survival and angiogenesis promoting effects of prokineticin-2 in cardiac cells were completely reversed by siRNA-PKR1, indicating PKR1 involvement. We thus, further investigated whether intramyocardial gene transfer of DNA encoding PKR1 may rescue the myocardium against myocardial infarction in mouse model. Transient PKR1 gene transfer after coronary ligation reduces mortality and preserves left ventricular function by promoting neovascularization and protecting cardiomyocytes without altering VEGF levels. In human end-stage failing heart samples, reduced PKR1 and prokineticin-2 transcripts and protein levels implicate a more important role for prokineticin-2/PKR1 signaling in heart. Our results suggest that PKR1 may represent a novel therapeutic target to limit myocardial injury following ischemic events.
  The FASEB Journal 10/2007; 21(11):2980-93. · 5.71 Impact Factor