PDE3A is a cyclic nucleotide phosphodiesterase that hydrolyzes the second messengers cAMP and cGMP, regulating their signaling in distinct cellular compartments including the plasma membrane, cytosol, nucleus, and sarcoplasmic reticulum. Beyond its catalytic role, PDE3A participates in an estrogen-dependent pro-apoptotic pathway: estrogen stabilizes a complex between PDE3A and SLFN12, promoting dephosphorylation of SLFN12 and activation of its ribonuclease activity, a mechanism potentially relevant to placenta remodeling. In platelets, thrombospondin-1 stimulates PDE3A activity to suppress cAMP signaling and promote hemostasis 1. During oocyte meiosis, PDE3A is inhibited by cGMP from cumulus cells, allowing cAMP accumulation and meiotic arrest; reductions in cGMP during the LH surge permit PDE3A-mediated cAMP hydrolysis and meiosis resumption 2. Gain-of-function PDE3A mutations cause hypertension with brachydactyly (HTNB), characterized by increased vascular smooth muscle resistance 3; surprisingly, these mutations confer cardiac protection against hypertension-induced damage through localized cAMP signaling changes 4. Clinically, PDE3A inhibitors—including cilostazol, dipyridamole, inamrinone, and anagrelide—are used for cardiovascular and hematologic conditions. Recent approaches to improve therapeutic specificity include inducing PDE3A-SLFN12 complex formation 5 and targeting compartmentalized cAMP signaling 6.