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dc.contributor.advisorde la Pompa, Jose Luis 
dc.contributor.advisorMacGrogan, Donal 
dc.contributor.authorFerreira Oliveira, Vera Lúcia
dc.date.accessioned2021-01-05T14:57:13Z
dc.date.available2021-01-05T14:57:13Z
dc.date.issued2020-12-18
dc.identifier.urihttp://hdl.handle.net/20.500.12105/11575
dc.description.abstractThe importance of the cardiac valves is apparent when one considers how often they are required to open and shut on a minute-to-minute basis. The complexity of their formation is underlined by the frequent involvement of valvular defects in several forms of congenital heart disease. Even though many of these defects are subtle, they often lead to disease and significant mortality later in life. Therefore, a comprehensive understanding of the mechanisms underlying valvulogenesis is of critical clinical importance. The chemokine receptor CXCR4 and its ligand CXCL12 are known to play important roles in cell mobility and behavior in various contexts. Targeted deletion of Cxcr4 using an endothelial driver has been shown to hamper the remodeling of the cardiac valves, which develop thickened leaflets. Nonetheless, the precise mechanism through which these chemotactic cytokines act during cardiac valvulogenesis remains unclear. The growth factor HBEGF is synthe The growth factor HBEGF is synthesized as a membrane bound proprotein that, upon cleavage, is released in order to activate nearby receptors, such as EGFR. Both soluble HBEGF (sHBEGF) itself and members of its pathway have been established as important players in valve formation. Several studies have demonstrated that disruption of members of the HBEGF-EGFR pathway results in valvular phenotypes similar to the ones observed upon Cxcr4 deletion. Our understanding of the molecular mechanisms underlying valve maturation is still limited. Even though many of the proteins and pathways involved have been studied in the last two decades, there is still much to be determined regarding the role they play and how they interact. Using novel mouse models, our aim was to obtain new knowledge about the CXCL12-CXCR4 and the HBEGF-EGFR signaling pathways during the remodeling phase of valvulogenesis. With that in mind, we began by corroborating how endocardial loss of Cxcr4 recapitulated the thickened leaflets phenotype previously found in other studies, with an associated increase in the proliferation of mesenchymal cells. This in vivo observation was further confirmed with the ex vivo system of outflow tract (OFT) heart explants. Treatment of control OFT explants with the CXCR4 antagonist AMD3100 confirmed the increase in mesenchymal cell proliferation. Another genetic tool we have employed is a mouse model that specifically overexpresses sHBEGF in endothelial cells, which we have generated using restriction cloning techniques. Surprisingly, we have found that the extra release of sHBEGF also led enlarged valves, accompanied by increased valve mesenchymal cell proliferation. Control OFT explants treated with recombinant sHBEGF also resulted in a pronounced increase in mesenchymal proliferation. Activation of different receptors or receptor dimers might explain the discrepancies between these observations and previous studies. These preliminary results point towards a novel role for CXCR4 during valve remodeling. Furthermore, they highlight the importance of the precise regulation of sHBEGF levels during this process. Further analysis of both of these pathways could help uncover how the process of valvulogenesis goes awry in the many different forms of congenital valve disease.es_ES
dc.description.sponsorshipThis work was performed in Dr. José Luis de la Pompa laboratory at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) in Madrid. This work was supported by the Ministerio de Ciencia, Innovación y Universidades from Spain (MCIU, grants SAF2016-78370-R, CB16/11/00399, CIBER CV, and RD16/0011/0021, TERCEL) and the Fundación BBVA (grant BIO14_298) and Fundación La Marató TV3 (grant 20153431) to J.L.dlPes_ES
dc.language.isoenges_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleUnraveling the molecular mechanisms behind the regulation of mesenchymal cell proliferation during cardiac valve remodelinges_ES
dc.typedoctoral thesises_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.doi10.4321/repisalud.11575
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España) 
dc.contributor.funderFundación BBVA 
dc.contributor.funderFundación La Marató TV3 
dc.description.peerreviewedes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Señalización Intercelular durante el Desarrollo y la Enfermedad Cardiovasculares_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/AF2016-78370-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/CB16/11/00399es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD16/0011/0021es_ES
dc.rights.accessRightsopen accesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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