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The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

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Abstract

Calcium (Ca2+) is a highly versatile second messenger that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and migration. By means of Ca2+ permeable channels, Ca2+ pumps and channels conducting other ions such as potassium and chloride, VSMC keep intracellular Ca2+ levels under tight control. In healthy quiescent contractile VSMC, two important components of the Ca2+ signaling pathways that regulate VSMC contraction are the plasma membrane voltage-operated Ca2+ channel of the high voltage-activated type (L-type) and the sarcoplasmic reticulum Ca2+ 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 Ca2+ 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) Ca2+ channels and the canonical transient receptor potential (TRPC) channels. The expression levels of intracellular Ca2+ release channels, pumps and Ca2+-activated proteins are also altered: the proliferative VSMC lose the RyR3 and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform 2a pump and reciprocally regulate isoforms of the ca2+/calmodulin-dependent protein kinase II. This review focuses on the changes in expression of Ca2+ signaling proteins associated with VSMC proliferation both in vitro and in vivo. The physiological implications of the altered expression of these Ca2+ signaling molecules, their contribution to VSMC dysfunction during vascular disease and their potential as targets for drug therapy will be discussed.

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Notes

  1. SOC channels can be considered a type of ROC channels. SOC channels are physiologically activated by the depletion of internal Ca2+ stores through IP3-mediated Ca2+ release, and also by pharmacological agents that deplete the internal Ca2+ stores without increasing the levels of IP3 such as the SERCA pump inhibitor thapsigargin. ROC channels include channels that are activated by signaling mechanisms downstream of membrane receptors, including second messengers such as IP3, diacylglycerol (DAG) and arachidonic acid (SMOC channels), Ca2+, cyclic nucleotides etc. In fact, the use of the ROC nomenclature which lumps together diverse ionic conductances is a reflection of our ignorance of the molecular identity and the exact mechanisms of activation of these ion channels.

  2. Some TRPC channels such as TRPC3 and TRPC7 are known to possess considerable constitutive activity [38], and it was clearly demonstrated that growth factors such as the epidermal growth factor (EGF) can increase the membrane expression of constitutively active TRPC channels through increased vesicular trafficking [18, 127]. Thus, it is reasonable to assume that strong hyperpolarization in VSMC would lead to increased constitutive activity of TRPC channels, and increased basal levels of cytoplasmic Ca2+.

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Acknowledgments

Funding for the authors work was supported by NIH grants to M.T (K22ES014729) and to H.A.S (R01 HL-4942612).

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  1. The Center for Cardiovascular Sciences, Albany Medical College, 47, New Scotland Avenue, MC-8, Albany, NY, 12208, USA

    Suzanne J. House, Marie Potier, Jonathan Bisaillon, Harold A. Singer & Mohamed Trebak

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  1. Suzanne J. House
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  2. Marie Potier
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Correspondence to Mohamed Trebak.

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House, S.J., Potier, M., Bisaillon, J. et al. The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease. Pflugers Arch - Eur J Physiol 456, 769–785 (2008). https://doi.org/10.1007/s00424-008-0491-8

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