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 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.

淋巴管诱导细胞接触抑制的分子机制尚不清楚。在这里，我们将 cGMP 依赖性磷酸二酯酶 2A (PDE2A) 确定为淋巴管而非血液内皮接触抑制的选择性调节剂。小鼠胚胎中Pde2a的条件性删除显示出严重的淋巴发育不良，而血管结构却保持不变。在缺乏 PDE2A 的情况下，人淋巴内皮细胞无法诱导成熟连接和细胞周期停滞，而 cGMP 水平升高，但 cAMP 水平不升高。 PDE2A 介导的 cGMP 水解的丧失会导致 p38 信号传导的激活和 NOTCH 信号传导的下调。然而，DLL4 诱导的 NOTCH 激活可恢复 PDE2A 缺陷的人淋巴内皮细胞的连接成熟和接触抑制。在出生后的小鼠肠系膜中，PDE2A 在集合淋巴瓣中特别富集，Pde2a的缺失会导致异常瓣膜的形成。我们的数据表明，PDE2A 在淋巴管成熟过程中选择性地微调 cGMP、p38 和 NOTCH 信号传导的串扰。