The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-mediated control of Notch signaling
The 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 blood endothelial contact inhibition. Conditional deletion of Pde2a in mouse embryos reveals severe lymphatic dysplasia, while blood vessel architecture remains unaltered. In the absence of PDE2A, human lymphatic endothelial cells fail to induce mature junctions and cell cycle arrest, while cGMP levels, but not cAMP levels, are increased. Loss of PDE2A-mediated cGMP hydrolysis leads to activation of p38 signaling and downregulation of NOTCH signaling. Vice versa, DLL4-induced NOTCH activation restores junctional maturation and contact inhibition in PDE2A-deficient lymphatic endothelial cells. In postnatal mesenteries, PDE2A is specifically enriched in collecting lymphatic valves and loss of Pde2a results in formation of abnormal valves. Our data demonstrate that PDE2A selectively finetunes a crosstalk of cGMP, p38 and NOTCH signaling during lymphatic vessel maturation.