Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility

Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G0–G1 phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G2/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor (MPF)), a key regulator of G2/M transition.

► PDE3A, not PDE3B, regulates cAMP pools which control cell cycle progression in murine VSMCs and oocytes.
► In VSMCs and oocytes, PDE3A-deficiency is associated with increased cAMP/PKA signaling and inhibition of MAPK signaling (but not inhibition of PI3K/Akt signaling in VSMCs).
► In VSMCs, PDE3A-deficiency is associated with changes in key cell cycle regulatory proteins, including upregulation of p53 and p21.
► In VSMCs, PDE3A-defiency is associated with inhibition of mitogen-induced and serum-induced DNA synthesis.
► siRNA-induced depletion of p53 completely restores DNA synthesis in 3A-KO VSMCs.