Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle

Cell Mol Life Sci. 2012 Jan;69(2):247-66. doi: 10.1007/s00018-011-0815-2. Epub 2011 Sep 27.


Vascular smooth muscle tone is controlled by a balance between the cellular signaling pathways that mediate the generation of force (vasoconstriction) and release of force (vasodilation). The initiation of force is associated with increases in intracellular calcium concentrations, activation of myosin light-chain kinase, increases in the phosphorylation of the regulatory myosin light chains, and actin-myosin crossbridge cycling. There are, however, several signaling pathways modulating Ca(2+) mobilization and Ca(2+) sensitivity of the contractile machinery that secondarily regulate the contractile response of vascular smooth muscle to receptor agonists. Among these regulatory mechanisms involved in the physiological regulation of vascular tone are the cyclic nucleotides (cAMP and cGMP), which are considered the main messengers that mediate vasodilation under physiological conditions. At least four distinct mechanisms are currently thought to be involved in the vasodilator effect of cyclic nucleotides and their dependent protein kinases: (1) the decrease in cytosolic calcium concentration ([Ca(2+)]c), (2) the hyperpolarization of the smooth muscle cell membrane potential, (3) the reduction in the sensitivity of the contractile machinery by decreasing the [Ca(2+)]c sensitivity of myosin light-chain phosphorylation, and (4) the reduction in the sensitivity of the contractile machinery by uncoupling contraction from myosin light-chain phosphorylation. This review focuses on each of these mechanisms involved in cyclic nucleotide-dependent relaxation of vascular smooth muscle under physiological conditions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium / physiology
  • Calcium-Transporting ATPases / metabolism
  • Calcium-Transporting ATPases / physiology
  • Humans
  • Mice
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / physiology
  • Myosin-Light-Chain Kinase / antagonists & inhibitors
  • Myosin-Light-Chain Kinase / metabolism
  • Myosin-Light-Chain Kinase / physiology
  • Myosin-Light-Chain Phosphatase / antagonists & inhibitors
  • Myosin-Light-Chain Phosphatase / metabolism
  • Myosin-Light-Chain Phosphatase / physiology
  • Nucleotides, Cyclic / metabolism
  • Nucleotides, Cyclic / pharmacology*
  • Nucleotides, Cyclic / physiology
  • Potassium Channels / agonists
  • Potassium Channels / metabolism
  • Potassium Channels / physiology
  • Rats
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum / physiology
  • Sodium-Calcium Exchanger / metabolism
  • Sodium-Calcium Exchanger / physiology
  • Vasodilation / drug effects*
  • Vasodilation / physiology
  • Vasodilator Agents / metabolism
  • Vasodilator Agents / pharmacology*


  • Nucleotides, Cyclic
  • Potassium Channels
  • Sodium-Calcium Exchanger
  • Vasodilator Agents
  • Myosin-Light-Chain Kinase
  • Myosin-Light-Chain Phosphatase
  • Calcium-Transporting ATPases
  • Calcium