EN
Endothelial regulation of cardiomyocyte microdomains (RP10)
Principial Investigators
Project Summary and Goals
Phosphodiesterase 2A (PDE2A) is a key regulator of cyclic nucleotide signaling and has recently emerged as an important determinant of endothelial cell function. We have previously shown that PDE2A differentially regulates cAMP and cGMP signaling in lymphatic and blood endothelial cells and is required for proper vascular development. Unexpectedly, our preliminary data demonstrate that endothelial-specific deletion of Pde2a also causes severe cardiac defects resembling those observed in global Pde2a knockout mice. Single-cell transcriptomic analyses revealed that Pde2a is expressed exclusively in cardiac endothelial cells, while its loss leads to profound transcriptional changes in neighboring cardiomyocytes, including dysregulation of genes involved in cyclic nucleotide microdomains. These findings suggest a previously unrecognized angiocrine mechanism by which endothelial cells control cardiomyocyte signaling and function.
In this project, we will test the hypothesis that endothelial PDE2A regulates cardiomyocyte cyclic nucleotide microdomains through angiocrine signaling and that disruption of this endothelial-cardiomyocyte communication contributes to cardiac dysfunction and arrhythmia. To address this, we will identify endothelial-derived signaling pathways that control cardiomyocyte microdomain organization, characterize their functional consequences in vitro and in vivo, and evaluate whether modulation of these angiocrine pathways can restore cardiomyocyte function in the adult heart.
Aims Addressed by the Doctoral Candidates
- Characterize mechanisms of endothelial-driven remodelling of cardiomyocyte microdomains in the adult mouse heart.
- Modulate angiocrine signaling to regulate cardiomyocyte function in vitro and in vivo.
Key Techniques
- Primary human endothelial cell and human iPSC-derived cardiomyocyte cultures
- Förster resonance energy transfer (FRET) biosensors
- Endothelial cell and cardiomyocyte functional assays (permeability assays, beating analysis)
- Confocal microscopy
- Single cell RNA sequencing and spatial transcriptomics
- Animal models to study cardiac development and disease
Publications
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The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-dependent notch signaling. Carlantoni C, Liekfeld LMH, Hemkemeyer SA, Schreier D, Saygi C, Kurelic R, Cardarelli S, Kalucka J, Schulte C, Beerens M, Mailer RK, Schaffer TE, Naro F, Pellegrini M, Nikolaev VO, Renne T, Frye M (2024). Dev Cell. 59:308-325 -
EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity. Frye M, Stritt S, Ortsäter H, Hernandez Vasquez M, Kaakinen M, Vicente A, Wiseman J, Eklund L, Martínez-Torrecuadrada JL, Vestweber D, Mäkinen T (2020). Elife. 9:e57732. -
Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Frye M, Taddei A, Dierkes C, Martinez-Corral I, Fielden M, Ortsäter H, Kazenwadel J, Calado DP, Ostergaard P, Salminen M, He L, Harvey NL, Kiefer F, Mäkinen T (2018). Nat Commun. 9:1511. -
Contribution of BKCa channels to vascular tone regulation by PDE3 and PDE4 is lost in heart failure. Idres S, Perrin G, Domergue V, Lefebvre F, Gomez S, Varin A, Fischmeister R, Leblais V, Manoury B (2019). Cardiovasc Res. 115:130-144. -
Influence of cell confluence on the cAMP signalling pathway in vascular smooth muscle cells. Belacel-Ouari M, Zhang L, Hubert F, Assaly R, Gerbier R, Jockers R, Dauphin F, Lechêne P, Fischmeister R, Manoury B, Leblais V (2017). Cell Signal. 35:118-128. -
Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. Frye M, Dierkes M, Küppers V, Vockel M, Tomm J, Zeuschner D, Rossaint J, Zarbock A, Koh GY, Peters K, Nottebaum AF, Vestweber D (2015). J Exp Med. 212:2267-2287.