The phosphodiesterase 2A regulates lymphatic endothelial development via cGMP-mediated control of Notch signaling

During vascular development endothelial junctions mature and vessel integrity is established to form the endothelial barrier. The molecular mechanisms by which lymphatic vessels induce cell contact inhibition are not understood. Here, we uncover 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 large 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 lymphatic valves. Our data demonstrate that PDE2A selectively modulates a crosstalk between cGMP, p38 and NOTCH signaling to finetune lymphatic development and suggest that PDE2A may be a druggable target to control lymphatic leakage and regeneration.