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

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.