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Título
Unraveling the molecular mechanisms behind the regulation of mesenchymal cell proliferation during cardiac valve remodeling
Autor(es)
Director
de la Pompa, Jose Luis CNIC | MacGrogan, Donal CNIC
Fecha de publicación
2020-12-18
Idioma
Inglés
Tipo de documento
doctoral thesis
Resumen
The 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.
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