Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle

Abstract

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.

Fig. 1

Mechanisms involved in the regulation of cyclic nucleotides levels and activation of kinases by these nucleotides. Green arrows stimulation, AC adenylate cyclase. pGC particulate guanylate cyclase, sGC soluble guanylate cyclase, R receptor, PDE phosphodiesterase, G G-protein, cAMP cyclic adenosine 3′,5′-monophosphate, cGMP cyclic guanosine 3′,5′-monophosphate, 5′AMP adenosine 5′-monophosphate, 5′GMP guanosine 5′-monophosphate, ATP adenosine 5′-triphosphate, GTP guanosine 5′-triphosphate, PKA cAMP-dependent protein kinase, PKG cGMP-dependent protein kinase

Fig. 2

Mechanisms involved in the decrease in intracellular calcium levels induced by cyclic nucleotide-dependent protein kinases. Green arrows stimulation, red arrows inhibition, SR sarcoplasmic reticulum, G guanosine-5′-triphosphate-binding protein, R G-protein coupled receptor, IP3 inositol 1, 4, 5-triphosphate, PIP2 phospholipid phosphatidylinositol 4,5-bisphosphate, PLC phospholipase C, PKA cAMP-dependent protein kinase, PKG cGMP-dependent protein kinase, SERCA sarcoplasmic reticulum Ca²⁺-ATPase, NCX Na⁺/Ca²⁺ exchanger, PMCA plasma membrane Ca²⁺-ATPase, VOCC voltage-operated Ca²⁺ channels

Fig. 3

Regulation of K⁺ channels by cyclic nucleotide-dependent protein kinases in VSM cells. Green arrows stimulation, red arrows inhibition, PKA cAMP-dependent protein kinase, PKG cGMP-dependent protein kinase

Fig. 4

Role of calcium in the regulation of the contractile state of VSM cells. CaM calmodulin, Ca-CaM calcium-calmodulin complex, MLCK myosin light-chain kinase, MLC ₂₀ 20-kDa regulatory light chain of myosin, P-MLC ₂₀ phosphorylated MLC₂₀, ROCK rho-activated protein kinase, MLCP myosin light-chain phosphatase, PKA cAMP-dependent protein kinase, PKG cGMP-dependent protein kinase, HSP20 20 kDa heat shock protein, P-HSP20 phosphorylated HSP20