The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease.
Calcium (Ca(2+)) is a highly versatile second messenger that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and migration. By means of Ca(2+) permeable channels, Ca(2+) pumps and channels conducting other ions such as potassium and chloride, VSMC keep intracellular Ca(2+) levels under tight control. In healthy quiescent contractile VSMC, two important components of the Ca(2+) signaling pathways that regulate VSMC contraction are the plasma membrane voltage-operated Ca(2+) channel of the high voltage-activated type (L-type) and the sarcoplasmic reticulum Ca(2+) release channel, Ryanodine Receptor (RyR). Injury to the vessel wall is accompanied by VSMC phenotype switch from a contractile quiescent to a proliferative motile phenotype (synthetic phenotype) and by alteration of many components of VSMC Ca(2+) signaling pathways. Specifically, this switch that culminates in a VSMC phenotype reminiscent of a non-excitable cell is characterized by loss of L-type channels expression and increased expression of the low voltage-activated (T-type) Ca(2+) channels and the canonical transient receptor potential (TRPC) channels. The expression levels of intracellular Ca(2+) release channels, pumps and Ca(2+)-activated proteins are also altered: the proliferative VSMC lose the RyR3 and the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase isoform 2a pump and reciprocally regulate isoforms of the ca(2+)/calmodulin-dependent protein kinase II. This review focuses on the changes in expression of Ca(2+) signaling proteins associated with VSMC proliferation both in vitro and in vivo. The physiological implications of the altered expression of these Ca(2+) signaling molecules, their contribution to VSMC dysfunction during vascular disease and their potential as targets for drug therapy will be discussed.
House
Suzanne J
SJ
The Center for Cardiovascular Sciences, Albany Medical College, 47, New Scotland Avenue, MC-8, Albany, NY, 12208, USA.
Potier
Marie
M
Bisaillon
Jonathan
J
Singer
Harold A
HA
Trebak
Mohamed
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D050052:TRPC Cation Channels / Q000378:metabolism; D014652:Vascular Diseases / Q000503:physiopathology*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015221:Potassium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D050052:TRPC Cation Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium