- freely available
J. Dev. Biol. 2013, 1(1), 20-31; doi:10.3390/jdb1010020
Published: 18 June 2013
Abstract: G protein-coupled receptors (GPCRs) form a large class of seven transmembrane (TM) domain receptors. The use of endogenous GPCR ligands to activate the stem cell maintenance or to direct cell differentiation would overcome many of the problems currently encountered in the use of stem cells, such as rapid in vitro differentiation and expansion or rejection in clinical applications. This review focuses on the definition of a new GPCR signaling pathway activated by peptide hormones, called “prokineticins”, in epicardium-derived cells (EPDCs). Signaling via prokineticin-2 and its receptor, PKR1, is required for cardiomyocyte survival during hypoxic stress. The binding of prokineticin-2 to PKR1 induces proliferation, migration and angiogenesis in endothelial cells. The expression of prokineticin and PKR1 increases during cardiac remodeling after myocardial infarction. Gain of function of PKR1 in the adult mouse heart revealed that cardiomyocyte-PKR1 signaling activates EPDCs in a paracrine fashion, thereby promoting de novo vasculogenesis. Transient PKR1 gene therapy after myocardial infarction in mice decreases mortality and improves heart function by promoting neovascularization, protecting cardiomyocytes and mobilizing WT1+ cells. Furthermore, PKR1 signaling promotes adult EPDC proliferation and differentiation to adopt endothelial and smooth muscle cell fate, for the induction of de novo vasculogenesis. PKR1 is expressed in the proepicardium and epicardial cells derived from mice kidneys. Loss of PKR1 causes deficits in EPDCs in the neonatal mice hearts and kidneys and impairs vascularization and heart and kidney function. Taken together, these data indicate a novel role for PKR1 in heart-kidney complex via EPDCs.
Over the last decade, stem/progenitor-cell therapy has emerged as an innovative approach to instigating cardiac repair and regeneration . Treatments based on cardiac progenitor cells have recently emerged as promising potential therapies for heart conditions . For cardiovascular therapy, pluripotent cardiac progenitor cells resident in the epicardium have several distinct advantages over other adult stem-cell types. They are autologous, tissue-specific and already committed to a cardiac fate [3,4]. Epicardium-derived cells (EPDCs) are present in the heart in several species, including zebrafish, mice and humans [5,6]. EPDCs offer an optimal target, since they give rise to cardiomyocytes and coronary vascular cells and provide a cocktail of growth factors that may contribute to regeneration of heart. However, the race is still on to find the “best” factors or drugs to control cell fate decisions within adult EPDCs for reconstitution of the myocardium and improving vascularization and function after myocardial damage.
G protein-coupled receptors (GPCRs) form a large class of seven-transmembrane domain receptors that transmit extracellular signals to cells by coupling to guanine nucleotide-binding proteins (G proteins) . GPCRs are the targets of about 20 to 50% of the drugs currently on the market and their genes account for 3 to 5% of the human genome. Many hormones and neurotransmitters use GPCRs to exert their cardiovascular effects [8,9]. Following the binding of a ligand on the extracellular side of the GPCR, conformational changes are induced, causing the intracellular loops to bind and activate the heterotrimeric G protein. The activated G protein dissociates from the receptor and its subunits (α and βγ) to induce second messenger signaling mediated by effector molecules, such as kinases, phospholipases, enzymes or channels. GPCRs are also involved in non G protein-mediated signaling via scaffold proteins, such as beta-arrestin . The role of GPCRs in the heart is illustrated in Figure 1. GPCRs may promote cardiac hypertrophy  or protect cardiomyocytes against hypoxic challenge [11,12] via Gαq signaling. Gα12 signaling interacts with the cytoplasmic domain of cadherins, resulting in the release of the transcriptional activator, β-catenin, which is a regulator of epicardial development . Gα13 signaling is involved in vessel formation . Gαs signaling regulates heart rate and contractility in response to catecholamine stimulation, but excessive Gαs signaling in the heart eventually induces myocardial hypertrophy, fibrosis and necrosis .
Relatively little is known about the role of GPCRs in the functional activities of EPDCs in both normal and disease conditions. Given the important roles played by GPCRs in cardiac regulation, it is vital to decipher the functions of GPCRs in EPDCs if we are to develop novel regenerative therapies to limit cardiovascular disease.
Only two factors have been identified as capable of stimulating adult EPDCs. Stimulation of the adult epicardium by thymosin beta 4 resulting in the differentiation of EPDC into vasculogenic cell types and cardiomyocytes has been demonstrated . More recently, prokineticin-2, a potent angiogenic hormone, has been shown to stimulate adult EPDCs . This review aims to provide an overview of what is currently known about the regulation of EPDC proliferation and differentiation by prokineticin receptor-1 (PKR1), a GPCR.
2. Prokineticins and Cognate Receptors
Prokineticins are small secreted proteins [18,19] . They were first identified in the gastrointestinal tract as potent agents mediating muscle contraction  and have been isolated from bovine milk . They comprise two classes: prokineticin-1 (PK1), originally called endocrine gland-derived vascular endothelial growth factor (EG-VEGF), based on the functional similarity to VEGF , and prokineticin-2 (PK2, also called Bv8). An alternatively spliced product of the PK2 gene encoding 21 additional amino acids compared with PK2 is designated PK2L (for PK2 long form) . Both PK2 and PK2L are expressed in heart, and only PK2 is expressed in kidney. PK1 and PK2 are approximately 50% homologous and contain carboxyl-terminal cysteine-rich domains that form five disulfide bridges. N terminal hexapeptide (AVITGA) and cysteine residues in the carboxy-terminal domain are crucial for their biological activities. Prokineticins are widely distributed in mammalian tissues . Prokineticins induce cell excitability (gut spasmogen, pain sensitization , circadian rhythm  and sleep ), cell motility (angiogenesis , neurogenesis , hematopoiesis , neovasculogenesis ) and complex behaviors (feeding , drinking , anxiety ). Prokineticin signaling has been implicated as a survival/mitogenic factor for various cells, including endothelial cells , neuronal cells,  enteric neural crest cells , granulocytic  and monocytic lineage , lymphocytes and hematopoietic stem cells .
Prokineticins bind to two cognate 7-transmembrane GPCRs. PKR1 and PKR2 share about 85% amino acid identity and encoded within distinct chromosomes in both mouse and human . Prokineticin-2 is the most potent agonist for both receptors . PKR2 is the dominant receptor in the adult brain, particularly in the hypothalamus, the olfactory ventricular regions and the limbic system. However, PKR1 is widely distributed in the periphery. These receptors couple to Gαq, Gαi and Gαs to mediate intracellular calcium mobilization, activation of MAPK, Akt kinases and cAMP accumulation, respectively . In cultured capillary endothelial cells derived from heart, prokineticin-2 via PKR1 induces proliferation, migration and vessel-like formation, activating Gα11/MAPK and Akt kinases . In cardiomyocytes, activation of overexpression of PKR1 protects cardiomyocytes against hypoxic insult, activating the PI3/Akt pathway .
3. Prokineticin Signaling in Myocardium and Epicardium Interaction
Transgenic mice overexpressing PKR1 in cardiomyocytes under the control of an α-MHC promoter display no spontaneous cardiomyocyte abnormalities . However, they have abnormally large numbers of epicardin-positive EPDCs, high capillary density and large numbers of coronary vessels. This study demonstrated that cardiomyocyte PKR1 signaling upregulates the ligand of PKR1, prokineticin-2, which in turn acts as a paracrine factor, inducing the proliferation and differentiation of EPDCs into endothelial and smooth muscle cells, thereby promoting neovascularization. This study described a new cardiomyocyte-epicardium interaction involving prokineticin/PKR1 signaling (Figure 2). Neonatal PKR1-null mutant mice have low levels of angiogenesis in the heart. These findings suggest that PKR1 is involved in postnatal de novo vascularization, rather than vasculogenesis during embryogenesis .
Prokineticin/PKR1 signaling also plays a cell-autonomous role in EPDC activation. Prokineticin/PKR1 signaling promotes the proliferation and differentiation of EPDCs. During normal development, EPDCs give rise to vascular precursors and adventitial fibroblasts. Prokineticin/PKR1 signaling reprograms neonatal and adult EPDCs, causing them to differentiate into a subset of embryonic cells, such as endothelial and smooth muscle cells, rather than fibroblasts. These data suggest that the PKR1 signaling inherent to EPDCs may determine the lineage of these cells .
4. Prokineticin Signaling in Myocardial Infarction (MI)
The expression of prokineticins and their receptors is upregulated 24 h after MI in mice (Figure 3). Moreover, Akt phosphorylation levels 30% higher in ischemic than in non-ischemic hearts indicates an activation of the cardioprotective signaling pathway, triggering the endogenous wound-healing process . In the mouse coronary ligation of MI model, intracardiac PKR1 gene transfer utilizing adenovirus (Adv) carrying PKR1 cDNA (Adv-PKR1) induced a 2.5-times increase in PKR1 level 24 h after MI, rising to a four-times increase 48 h after MI (Figure 3).
PKR1 gene transfer decreased MI size, improved left ventricular performance and resulted in lower mortality than in untreated control mice . Neither VEGF protein nor VEGF-A transcripts, 164 and 188, displayed differences in abundance between PKR1-treated hearts and vehicle-treated hearts after MI, consistent with observations in cultured endothelium cells after prokineticin-2 treatment. Thus, transient PKR1 transfection induces capillary network growth without increasing VEGF levels. The cardioprotector signaling pathway, involving Akt activation, has been shown to be significantly more active in vivo in PKR1-treated hearts than in Adv-control vector-treated hearts one week after coronary ligation . These data thus suggest that transient PKR1 gene transfer has beneficial effects on recovery from myocardial infarction.
Transient gene therapy with PKR1 enhances angiogenesis and decreases apoptosis after MI . The PKR1-mediated cardioprotective effects may involve the prevention of cardiomyocyte apoptosis. The promotion of collateral vessel formation, to ensure sufficient tissue oxygenation, would also preserve myocardial function. PKR1-mediated angiogenesis may, therefore, play an important role in keeping sufficient numbers of cardiomyocytes alive for successful cardioprotection, after its initial anti-apoptotic effect. A third mechanism might involve a contribution of the inflammation itself to PKR1-mediated angiogenesis in infarcted hearts. Indeed, PKR1 signaling is involved in inflammation, monocyte activation and macrophage differentiation , and PKR1-knockout mice display a lack of inflammation in response to PK2 stimulation [25,39]. However, the number of cells infiltrating the scar area after myocardial infarction did not differ between mice transfected with the PKR1 gene and control mice after MI, arguing against an indirect effect of PKR1 through the inflammatory response. Finally, PKR1 could also preserve myocardial function by inducing WT1 and epicardin positive progenitor cell expansion and migration, as shown in Figure 4.
5. Prokineticin Signaling in the Epicardium-Kidney Axis
Several studies have shown that many genes are expressed in both epicardium and kidney progenitors. The deletion of these proepicardial genes, such as WT1 , tcf21 (epicardin) [41,42], the nephrin  gene and T-box transcription factor 18 (Tbx18) [44,45] in mice has been shown to lead to both heart and kidney defects. WT1 induces epithelial-to-mesenchymal transition (EMT) during the formation of cardiac progenitors from the epicardial field . WT1 regulates the reverse process (MET) in kidney mesenchyme. Similarly inactivating mutation of WT1 in humans leads to disease(s) associated with both  and heart functions . These findings suggest that the development of the epicardium and kidney may be connected via the proepicardium . The proepicardium has been shown to expresses PKR1 (Figure 5), which is required for epicardial and glomerular differentiation [40,50]. Moreover, the expression of PKR1 genes has been demonstrated in both epicardial and kidney progenitors. In particular, PKR1 expression has been demonstrated in epicardin-positive progenitor cells resident in the heart and kidney. Neonatal PKR1-null mutant mice have lower capillary numbers and densities in the heart and kidneys than their wild-type littermates (Figure 5). Epicardin-positive progenitor cells are significantly less abundant in the PKR1-null mutant epicardium, subepicardium and glomerulus than in the corresponding wild-type tissues . In epicardin positive progenitor cells from wild-type kidneys (prepared on postnatal day 1), prokineticin-2 induces the differentiation of these cells into both endothelial and smooth muscle cells. By contrast, these effects of prokineticin are completely abolished in these cells derived from mutant kidneys (Figure 5). These data demonstrate that PKR1 signaling controls the differentiation of the epicardin positive progenitor cells potentially involved in glomerular and epicardial angiogenesis. Adult PKR1-null mutant mice develop abnormalities of cardiac and renal function . PKR1 loss leads to cardiomegaly, severe interstitial fibrosis and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, small numbers of glomerular capillaries, urinary phosphate excretion and proteinuria in older individuals. Thus, PKR1 inactivation in mice leads to defects of progenitor cell proliferation and differentiation, potentially linking cardiac and renal damage.
6. Concluding Remarks
Many studies have focused on angiogenesis in cancer and circadian clock regulation, whereas explorations of the role of the prokineticin signal transduction pathway in cardiovascular disease have only recently begun. Such studies in cardiovascular diseases have suggested that PKR1 plays an important role in EPDCs, endothelial cells and cardiomyocytes. The EPDC pool is a mixture of cells with different gene expression profiles. Several recent lineage-tracing experiments have demonstrated the presence of multipotent progenitor cells within the activated adult epicardium, but there have been few functional studies directly manipulating gene expression specifically in the adult epicardium, to evaluate its contribution to cardiac regeneration and repair. Current studies on cardiac regeneration via EPDCs have revealed discrepancies, with several possible origins: (1) different EPDC pools may generate different types of cardiac cells; (2) all the EPDCs are multipotent and the genetic engineering of these cells or the provision of particular growth stimuli, such as PKR1, can elicit the myogenic or vasculogenic potential of these cells; (3) different classes of vertebrates may have different systems of EPDC regulation. WT1+ epicardial progenitor cells give rise to smooth muscle cells of the coronary vasculature and to fibroblasts and contribute 4% of the total number of cardiomyocytes . Similar results have been obtained for EPDCs expressing the Tbx18 gene . Tcf21+ epicardial cells in mouse  and zebrafish  give rise to intracardiac fibroblasts, but not to coronary smooth muscle or endothelial cells. However, scleraxis- and semaphorin3D-expressing EPDCs in the developing mouse heart give rise to endothelial cells of the coronary vasculature and contribute 6.6% and 0.36% of the total number of cardiomyocytes, respectively . We hypothesize that although EPDCs are not necessarily a natural source of both vasculogenic cells and cardiomyocytes; the activation of PKR1 or genetic engineering of these cells with the PKR1 gene can be used to elicit the myogenic and vasculogenic potential of EPDCs and can induce the secretion of prosurvival factors in these cells, contributing to the maintenance/regeneration of damaged hearts. We are currently carrying out experimental studies in our laboratory to assess the feasibility of this approach. We will then consider the role of PKR1 in renal epicardin positive progenitor cell differentiation into renal cells. Overall, the available data show that PKR1 is involved in postnatal cardiac and renal neovascularization, but the role of prokineticins in the pathophysiology of human heart and kidney diseases remains to be explored.
This work was supported by Centre National de la Recherche Scientifique (CNRS), Fondation Recherche Medical (FRM), Région Alsace and LabEX/Medalis.
Conflict of Interest
The authors declare no conflict of interest.
References and Notes
- Zimmermann, W.H.; Eschenhagen, T. Questioning the relevance of circulating cardiac progenitor cells in cardiac regeneration. Cardiovasc. Res. 2005, 68, 344–346, doi:10.1016/j.cardiores.2005.09.010.
- Gonzales, C.; Pedrazzini, T. Progenitor cell therapy for heart disease. Exp. Cell. Res. 2009, 315, 3077–3085, doi:10.1016/j.yexcr.2009.09.006.
- Smart, N.; Bollini, S.; Dube, K.N.; Vieira, J.M.; Zhou, B.; Davidson, S.; Yellon, D.; Riegler, J.; Price, A.N.; Lythgoe, M.F.; Pu, W.T.; Riley, P.R. De novo cardiomyocytes from within the activated adult heart after injury. Nature 2011, 474, 640–644, doi:10.1038/nature10188.
- Limana, F.; Capogrossi, M.C.; Germani, A. The epicardium in cardiac repair: from the stem cell view. Pharmacol. Ther. 2011, 129, 82–96, doi:10.1016/j.pharmthera.2010.09.002.
- Limana, F.; Zacheo, A.; Mocini, D.; Mangoni, A.; Borsellino, G.; Diamantini, A.; De Mori, R.; Battistini, L.; Vigna, E.; Santini, M.; Loiaconi, V.; Pompilio, G.; Germani, A.; Capogrossi, M.C. Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ. Res. 2007, 101, 1255–1265.
- Lepilina, A.; Coon, A.N.; Kikuchi, K.; Holdway, J.E.; Roberts, R.W.; Burns, C.G.; Poss, K.D. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 2006, 127, 607–619.
- Rockman, H.A.; Lefkowitz, R.J. Introduction to the series on novel aspects of cardiovascular G protein-coupled receptor signaling. Circ. Res. 2011, 109, 202–204, doi:10.1161/CIRCRESAHA.110.231126.
- Tang, C.M.; Insel, P.A. GPCR expression in the heart; "new" receptors in myocytes and fibroblasts. Trends Cardiovasc. Med. 2004, 14, 94–99, doi:10.1016/j.tcm.2003.12.007.
- Marinissen, M.J.; Gutkind, J.S. G protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci. 2001, 22, 368–376, doi:10.1016/S0165-6147(00)01678-3.
- Wettschureck, N.; Rutten, H.; Zywietz, A.; Gehring, D.; Wilkie, T.M.; Chen, J.; Chien, K.R.; Offermanns, S. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes. Nat. Med. 2001, 7, 1236–1240, doi:10.1038/nm1101-1236.
- Nebigil, C.G.; Jaffre, F.; Messaddeq, N.; Hickel, P.; Monassier, L.; Launay, J.M.; Maroteaux, L. Overexpression of the serotonin 5-HT2B receptor in heart leads to abnormal mitochondrial function and cardiac hypertrophy. Circulation 2003, 107, 3223–3229, doi:10.1161/01.CIR.0000074224.57016.01.
- Howes, A.L.; Miyamoto, S.; Adams, J.W.; Woodcock, E.A.; Brown, J.H. Galphaq expression activates EGFR and induces Akt mediated cardiomyocyte survival: dissociation from Galphaq mediated hypertrophy. J. Mol. Cell. Cardiol. 2006, 40, 597–604, doi:10.1016/j.yjmcc.2005.12.003.
- Kaplan, D.D.; Meigs, T.E.; Casey, P.J. Distinct regions of the cadherin cytoplasmic domain are essential for functional interaction with Galpha 12 and beta-catenin. J. Biol. Chem. 2001, 276, 44037–44043, doi:10.1074/jbc.M106121200.
- Offermanns, S.; Mancino, V.; Revel, J.P.; Simon, M.I. Vascular system defects and impaired cell chemokinesis as a result of Galpha13 deficiency. Science 1997, 275, 533–536, doi:10.1126/science.275.5299.533.
- Gaudin, C.; Ishikawa, Y.; Wight, D.C.; Mahdavi, V.; Nadal-Ginard, B.; Wagner, T.E.; Vatner, D.E.; Homcy, C.J. Overexpression of Gs alpha protein in the hearts of transgenic mice. J. Clin. Invest. 1995, 95, 1676–1683, doi:10.1172/JCI117843.
- Smart, N.; Risebro, C.A.; Melville, A.A.; Moses, K.; Schwartz, R.J.; Chien, K.R.; Riley, P.R. Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature 2007, 445, 177–182, doi:10.1038/nature05383.
- Urayama, K.; Guilini, C.; Turkeri, G.; Takir, S.; Kurose, H.; Messaddeq, N.; Dierich, A.; Nebigil, C.G. Prokineticin receptor-1 induces neovascularization and epicardial-derived progenitor cell differentiation. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 841–849, doi:10.1161/ATVBAHA.108.162404.
- Kaser, A.; Winklmayr, M.; Lepperdinger, G.; Kreil, G. The AVIT protein family. Secreted cysteine-rich vertebrate proteins with diverse functions. EMBO Rep. 2003, 4, 469–473, doi:10.1038/sj.embor.embor830.
- Nebigil, C.G. Prokineticin receptors in cardiovascular function: foe or friend? Trends Cardiovasc. Med. 2009, 19, 55–60.
- Li, M.; Bullock, C.M.; Knauer, D.J.; Ehlert, F.J.; Zhou, Q.Y. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol. Pharmacol. 2001, 59, 692–698.
- Masuda, Y.; Takatsu, Y.; Terao, Y.; Kumano, S.; Ishibashi, Y.; Suenaga, M.; Abe, M.; Fukusumi, S.; Watanabe, T.; Shintani, Y.; Yamada, T.; Hinuma, S.; Inatomi, N.; Ohtaki, T.; Onda, H.; Fujino, M. Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G protein-coupled receptors. Biochem. Biophys. Res. Commun. 2002, 293, 396–402, doi:10.1016/S0006-291X(02)00239-5.
- LeCouter, J.; Lin, R.; Ferrara, N. The role of EG-VEGF in the regulation of angiogenesis in endocrine glands. Cold Spring Harb Symp. Quant. Biol. 2002, 67, 217–221, doi:10.1101/sqb.2002.67.217.
- Chen, J.; Kuei, C.; Sutton, S.; Wilson, S.; Yu, J.; Kamme, F.; Mazur, C.; Lovenberg, T.; Liu, C. Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1. Mol. Pharmacol. 2005, 67, 2070–2076, doi:10.1124/mol.105.011619.
- Soga, T.; Matsumoto, S.; Oda, T.; Saito, T.; Hiyama, H.; Takasaki, J.; Kamohara, M.; Ohishi, T.; Matsushime, H.; Furuichi, K. Molecular cloning and characterization of prokineticin receptors. Biochim. Biophys. Acta 2002, 1579, 173–179, doi:10.1016/S0167-4781(02)00546-8.
- Negri, L.; Lattanzi, R.; Giannini, E.; Colucci, M.; Margheriti, F.; Melchiorri, P.; Vellani, V.; Tian, H.; De Felice, M.; Porreca, F. Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior. J. Neurosci. 2006, 26, 6716–6727, doi:10.1523/JNEUROSCI.5403-05.2006.
- Li, J.D.; Hu, W.P.; Boehmer, L.; Cheng, M.Y.; Lee, A.G.; Jilek, A.; Siegel, J.M.; Zhou, Q.Y. Attenuated circadian rhythms in mice lacking the prokineticin 2 gene. J. Neurosci. 2006, 26, 11615–11623, doi:10.1523/JNEUROSCI.3679-06.2006.
- Hu, W.P.; Li, J.D.; Zhang, C.; Boehmer, L.; Siegel, J.M.; Zhou, Q.Y. Altered circadian and homeostatic sleep regulation in prokineticin 2-deficient mice. Sleep 2007, 30, 247–256.
- LeCouter, J.; Ferrara, N. EG-VEGF and the concept of tissue-specific angiogenic growth factors. Semin. Cell. Dev. Biol. 2002, 13, 3–8, doi:10.1006/scdb.2001.0284.
- Ng, K.L.; Li, J.D.; Cheng, M.Y.; Leslie, F.M.; Lee, A.G.; Zhou, Q.Y. Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science 2005, 308, 1923–1927, doi:10.1126/science.1112103.
- LeCouter, J.; Zlot, C.; Tejada, M.; Peale, F.; Ferrara, N. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc. Natl. Acad. Sci. USA 2004, 101, 16813–16818.
- Negri, L.; Lattanzi, R.; Giannini, E.; De Felice, M.; Colucci, A.; Melchiorri, P. Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats. Br. J. Pharmacol. 2004, 142, 181–191, doi:10.1038/sj.bjp.0705686.
- Li, J.D.; Hu, W.P.; Zhou, Q.Y. Disruption of the circadian output molecule prokineticin 2 results in anxiolytic and antidepressant-like effects in mice. Neuropsychopharmacology 2009, 34, 367–373, doi:10.1038/npp.2008.61.
- Guilini, C.; Urayama, K.; Turkeri, G.; Dedeoglu, D.B.; Kurose, H.; Messaddeq, N.; Nebigil, C.G. Divergent roles of prokineticin receptors in the endothelial cells: Angiogenesis and fenestration. Am. J. Physiol. Heart Circ. Physiol. 2010, 298, H844–H852, doi:10.1152/ajpheart.00898.2009.
- Ngan, E.S.; Lee, K.Y.; Sit, F.Y.; Poon, H.C.; Chan, J.K.; Sham, M.H.; Lui, V.C.; Tam, P.K. Prokineticin-1 modulates proliferation and differentiation of enteric neural crest cells. Biochim. Biophys. Acta 2007, 1773, 536–545, doi:10.1016/j.bbamcr.2007.01.013.
- Giannini, E.; Lattanzi, R.; Nicotra, A.; Campese, A.F.; Grazioli, P.; Screpanti, I.; Balboni, G.; Salvadori, S.; Sacerdote, P.; Negri, L. The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain. Proc. Natl. Acad. Sci. USA 2009, 106, 14646–14651, doi:10.1073/pnas.0903720106.
- Dorsch, M.; Qiu, Y.; Soler, D.; Frank, N.; Duong, T.; Goodearl, A.; O'Neil, S.; Lora, J.; Fraser, C.C. PK1/EG-VEGF induces monocyte differentiation and activation. J. Leukoc. Biol. 2005, 78, 426–434, doi:10.1189/jlb.0205061.
- Ngan, E.S.; Tam, P.K. Prokineticin-signaling pathway. Int. J. Biochem. Cell Biol. 2008, 40, 1679–1684, doi:10.1016/j.biocel.2008.03.010.
- Urayama, K.; Guilini, C.; Messaddeq, N.; Hu, K.; Steenman, M.; Kurose, H.; Ert, G.; Nebigil, C.G. The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis. FASEB J. 2007, 21, 2980–2993, doi:10.1096/fj.07-8116com.
- Martucci, C.; Franchi, S.; Giannini, E.; Tian, H.; Melchiorri, P.; Negri, L.; Sacerdote, P. Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages. Br. J. Pharmacol. 2006, 147, 225–234, doi:10.1038/sj.bjp.0706467.
- Essafi, A.; Webb, A.; Berry, R.L.; Slight, J.; Burn, S.F.; Spraggon, L.; Velecela, V.; Martinez-Estrada, O.M.; Wiltshire, J.H.; Roberts, S.G.; Brownstein, D.; Davies, J.A.; Hastie, N.D.; Hohenstein, P. A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression. Dev. Cell 2011, 21, 559–574, doi:10.1016/j.devcel.2011.07.014.
- Acharya, A.; Baek, S.T.; Banfi, S.; Eskiocak, B.; Tallquist, M.D. Efficient inducible Cre-mediated recombination in Tcf21 cell lineages in the heart and kidney. Genesis 2011, 49, 870–877, doi:10.1002/dvg.20750.
- Robb, L.; Mifsud, L.; Hartley, L.; Biben, C.; Copeland, N.G.; Gilbert, D.J.; Jenkins, N.A.; Harvey, R.P. Epicardin: A novel basic helix-loop-helix transcription factor gene expressed in epicardium, branchial arch myoblasts, and mesenchyme of developing lung, gut, kidney, and gonads. Dev. Dyn. 1998, 213, 105–113, doi:10.1002/(SICI)1097-0177(199809)213:1<105::AID-AJA10>3.0.CO;2-1.
- Wagner, N.; Morrison, H.; Pagnotta, S.; Michiels, J.F.; Schwab, Y.; Tryggvason, K.; Schedl, A.; Wagner, K.D. The podocyte protein nephrin is required for cardiac vessel formation. Hum. Mol. Genet. 2011, 20, 2182–2194, doi:10.1093/hmg/ddr106.
- Airik, R.; Bussen, M.; Singh, M.K.; Petry, M.; Kispert, A. Tbx18 regulates the development of the ureteral mesenchyme. J. Clin. Invest. 2006, 116, 663–674, doi:10.1172/JCI26027.
- Christoffels, V.M.; Grieskamp, T.; Norden, J.; Mommersteeg, M.T.; Rudat, C.; Kispert, A. Tbx18 and the fate of epicardial progenitors. Nature 2009, 458, E8–E9; Discussion E9–E10, doi:10.1038/nature07916.
- Martinez-Estrada, O.M.; Lettice, L.A.; Essafi, A.; Guadix, J.A.; Slight, J.; Velecela, V.; Hall, E.; Reichmann, J.; Devenney, P.S.; Hohenstein, P.; Hosen, N.; Hill, R.E.; Munoz-Chapuli, R.; Hastie, N.D. Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nat. Genet. 2010, 42, 89–93.
- Hohenstein, B.; Hausknecht, B.; Boehmer, K.; Riess, R.; Brekken, R.A.; Hugo, C.P. Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int. 2006, 69, 1654–1661, doi:10.1038/sj.ki.5000294.
- Suri, M.; Kelehan, P.; O'Neill, D.; Vadeyar, S.; Grant, J.; Ahmed, S.F.; Tolmie, J.; McCann, E.; Lam, W.; Smith, S.; Fitzpatrick, D.; Hastie, N.D.; Reardon, W. WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. Am. J. Med. Genet. A 2007, 143A, 2312–2320, doi:10.1002/ajmg.a.31924.
- Perez-Pomares, J.M.; Carmona, R.; Gonzalez-Iriarte, M.; Atencia, G.; Wessels, A.; Munoz-Chapuli, R. Origin of coronary endothelial cells from epicardial mesothelium in avian embryos. Int J. Dev. Biol. 2002, 46, 1005–1013.
- Pombal, M.A.; Carmona, R.; Megias, M.; Ruiz, A.; Perez-Pomares, J.M.; Munoz-Chapuli, R. Epicardial development in lamprey supports an evolutionary origin of the vertebrate epicardium from an ancestral pronephric external glomerulus. Evol. Dev. 2008, 10, 210–216, doi:10.1111/j.1525-142X.2008.00228.x.
- Boulberdaa, M.; Turkeri, G.; Urayama, K.; Dormishian, M.; Szatkowski, C.; Zimmer, L.; Messaddeq, N.; Laugel, V.; Dolle, P.; Nebigil, C.G. Genetic inactivation of prokineticin receptor-1 leads to heart and kidney disorders. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 842–850, doi:10.1161/ATVBAHA.110.222323.
- Boulberdaa, M.; Urayama, K.; Nebigil, C.G. Prokineticin receptor 1 (PKR1) signalling in cardiovascular and kidney functions. Cardiovasc. Res. 2011, 92, 191–198, doi:10.1093/cvr/cvr228.
- Noguchi, H.; Ueda, M.; Matsumoto, S.; Kobayashi, N.; Hayashi, S. BETA2/NeuroD protein transduction requires cell surface heparan sulfate proteoglycans. Hum. Gene Ther 2007, 18, 10–17, doi:10.1089/hum.2006.118.
- Zhou, B.; Ma, Q.; Rajagopal, S.; Wu, S.M.; Domian, I.; Rivera-Feliciano, J.; Jiang, D.; von Gise, A.; Ikeda, S.; Chien, K.R.; Pu, W.T. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 2008, 454, 109–113, doi:10.1038/nature07060.
- Cai, C.L.; Martin, J.C.; Sun, Y.; Cui, L.; Wang, L.; Ouyang, K.; Yang, L.; Bu, L.; Liang, X.; Zhang, X.; Stallcup, W.B.; Denton, C.P.; McCulloch, A.; Chen, J.; Evans, S.M. A myocardial lineage derives from Tbx18 epicardial cells. Nature 2008, 454, 104–108, doi:10.1038/nature06969.
- Acharya, A.; Baek, S.T.; Huang, G.; Eskiocak, B.; Goetsch, S.; Sung, C.Y.; Banfi, S.; Sauer, M.F.; Olsen, G.S.; Duffield, J.S.; Olson, E.N.; Tallquist, M.D. The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 2012, 139, 2139–2149, doi:10.1242/dev.079970.
- Kikuchi, K.; Gupta, V.; Wang, J.; Holdway, J.E.; Wills, A.A.; Fang, Y.; Poss, K.D. tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. Development 2011, 138, 2895–2902, doi:10.1242/dev.067041.
- Katz, T.C.; Singh, M.K.; Degenhardt, K.; Rivera-Feliciano, J.; Johnson, R.L.; Epstein, J.A.; Tabin, C.J. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev. Cell. 2012, 22, 639–650, doi:10.1016/j.devcel.2012.01.012.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).