PDE2A is a cyclic nucleotide phosphodiesterase that hydrolyzes both cAMP and cGMP, functioning as a critical regulator of intracellular signaling across multiple tissues and disease contexts. PDE2A exhibits tissue-specific expression, with particular enrichment in venous and capillary endothelial cells rather than arterial endothelium 1, and plays specialized roles in mitochondrial function and lymphatic development. Mechanistically, PDE2A regulates cGMP-dependent signaling pathways; in lymphatic endothelial cells, PDE2A controls junctional maturation and contact inhibition through cGMP hydrolysis, which modulates p38 and NOTCH signaling 2. In cardiac tissue, PDE2A gene therapy restores altered cAMP compartmentation in subcellular microdomains, reducing cardiac hypertrophy, fibrosis, and arrhythmias 3. Disease associations include psychiatric disorders and cancer progression. Mendelian randomization analysis identified PDE2A as protective against Tourette syndrome and schizophrenia 4, while neuroimaging studies demonstrated region-specific PDE2A mRNA reductions in psychiatric patients, particularly in the amygdala across schizophrenia, depression, and bipolar disorder 5. In hepatocellular carcinoma, low PDE2A expression paradoxically predicts poor prognosis and promotes proliferation through altered mitochondrial morphology and ATP metabolism 6. Additionally, PDE2A emerges as a prognostic biomarker in multiple cancer types with immunotherapeutic potential 7.