2026-06-30T01:54:31Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/133062024-09-27T07:57:15Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Torregrosa-Carrión, Rebeca
author
Luna-Zurita, Luis
author
Garcia-Marques, Fernando
author
D'Amato, Gaetano
author
Piñeiro-Sabarís, Rebeca
author
Bonzon-Kulichenko, Elena
author
Vazquez, Jesus
author
de la Pompa, Jose Luis
funder
Fundación La Caixa
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Fundación BBVA
funder
Fundación La Marató TV3
funder
Instituto de Salud Carlos III
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Fundación ProCNIC
2021-08-24T07:15:16Z
2021-08-24T07:15:16Z
2019-09
Mol Cell Proteomics. 2019; 18(9):1782-95
10.1074/mcp.RA119.001492
1535-9484
Molecular & cellular proteomics : MCP
31249105
http://hdl.handle.net/20.500.12105/13306
The endocardium is a specialized endothelium that lines the inner surface of the heart. Functional studies in mice and zebrafish have established that the endocardium is a source of instructive signals for the development of cardiac structures, including the heart valves and chambers. Here, we characterized the NOTCH-dependent endocardial secretome by manipulating NOTCH activity in mouse embryonic endocardial cells (MEEC) followed by mass spectrometry-based proteomics. We profiled different sets of soluble factors whose secretion not only responds to NOTCH activation but also shows differential ligand specificity, suggesting that ligand-specific inputs may regulate the expression of secreted proteins involved in different cardiac development processes. NOTCH signaling activation correlates with a transforming growth factor-β2 (TGFβ2)-rich secretome and the delivery of paracrine signals involved in focal adhesion and extracellular matrix (ECM) deposition and remodeling. In contrast, NOTCH inhibition is accompanied by the up-regulation of specific semaphorins that may modulate cell migration. The secretome protein expression data showed a good correlation with gene profiling of RNA expression in embryonic endocardial cells. Additional characterization by in situ hybridization in mouse embryos revealed expression of various NOTCH candidate effector genes (Tgfβ2, Loxl2, Ptx3, Timp3, Fbln2, and Dcn) in heart valve endocardium and/or mesenchyme. Validating these results, mice with conditional Dll4 or Jag1 loss-of-function mutations showed gene expression alterations similar to those observed at the protein level in vitro These results provide the first description of the NOTCH-dependent endocardial secretome and validate MEEC as a tool for assaying the endocardial secretome response to a variety of stimuli and the potential use of this system for drug screening.
eng
NOTCH Activation Promotes Valve Formation by Regulating the Endocardial Secretome.
journal article
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NOTCHActivationPromotesValve_2019.pdf.txt