Phosphodiesterase 3A expression and activity in the murine vasculature is influenced by NO-sensitive guanylyl cyclase

Pflugers Arch. 2018 Apr;470(4):693-702. doi: 10.1007/s00424-017-2106-8. Epub 2018 Jan 2.

Abstract

Phosphodiesterase 3 (PDE3) exists in two isoforms (PDE3A and PDE3B) and is known to act as cGMP-inhibited cAMP-degrading PDE. Therefore, PDE3 may likely be involved in the interaction between the two second messenger pathways. NO-sensitive guanylyl cyclase (NO-GC) is the most important cytosolic generator of cGMP. Here, we investigated the effect of NO-GC deletion on PDE3A-mediated signaling in animals lacking NO-GC either globally (GCKO) or specifically in smooth muscle cells (SMC-GCKO). PDE3A expression is detected in murine aortic smooth muscle, platelets, and heart tissue. Expression and activity of PDE3A in aortae from GCKO and SMC-GCKO mice was reduced by approx. 50% compared to that in control animals. PDE3A downregulation can be linked to the reduction in NO-GC and is not an effect of the increased blood pressure levels resulting from NO-GC deletion. Despite the different PDE3A expression levels, smooth muscle relaxation induced by forskolin to stimulate cAMP signaling was similar in all genotypes. Basal and forskolin-stimulated cAMP levels in aortic tissue were not different between KO and control strains. However, the potency of milrinone, a selective inhibitor of PDE3A, to induce relaxation was higher in aortae from GCKO and SMC-GCKO than that in aorta from control animals. These data were corroborated by the effect of milrinone in vivo, which led to an increase in systolic blood pressure in both KO strains but not in control mice. We conclude that NO-GC modulates PDE3A expression and activity in SMC in vivo conceivably to preserve functional cAMP signaling.

Keywords: Nitric oxide; Phosphodiesterase; Transgenic mice; Vasorelaxation; cGMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / metabolism*
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Guanylate Cyclase / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Milrinone / pharmacology
  • Muscle Relaxation / drug effects
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Nitric Oxide / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Colforsin
  • Nitric Oxide
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Pde3a protein, mouse
  • Guanylate Cyclase
  • Cyclic GMP
  • Milrinone