The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-dependent notch signaling

Dev Cell. 2023 Dec 23:S1534-5807(23)00652-4. doi: 10.1016/j.devcel.2023.12.002. Online ahead of print.ABSTRACTThe molecular mechanisms by which lymphatic vessels induce cell contact inhibition are not understood. Here, we identify the cGMP-dependent phosphodiesterase 2A (PDE2A) as a selective regulator of lymphatic but not of blood endothelial contact inhibition. Conditional deletion of Pde2a in mouse embryos reveals severe lymphatic dysplasia, whereas blood vessel architecture remains unaltered. In the absence of PDE2A, human lymphatic endothelial cells fail to induce mature junctions and cell cycle arrest, whereas cGMP levels, but not cAMP levels, are increased. Loss of PDE2A-mediated cGMP hydrolysis leads to the activation of p38 signaling and downregulation of NOTCH signaling. However, DLL4-induced NOTCH activation restores junctional maturation and contact inhibition in PDE2A-deficient human lymphatic endothelial cells. In postnatal mouse mesenteries, PDE2A is specifically enriched in collecting lymphatic valves, and loss of Pde2a results in the formation of abnormal valves. Our data demonstrate that PDE2A selectively finetunes a crosstalk of cGMP, p38, and NOTCH signaling during lymphatic vessel maturation.PMID:38159569 | DOI:10.1016/j.devcel.2023.12.002

Source: Developmental Cell - December 30, 2023 Category: Cytology Authors: Claudia Carlantoni Leon M H Liekfeld Sandra A Hemkemeyer Danny Schreier Ceren Saygi Roberta Kurelic Silvia Cardarelli Joanna Kalucka Christian Schulte Manu Beerens Reiner K Mailer Tilman E Sch äffer Fabio Naro Manuela Pellegrini Viacheslav O Nikolaev Tho Source Type: research