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

Abstract

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.

Fig. 1

Ion channel modulation during phenotypic switching of VSMC. In contractile VSMC, extracellular Ca²⁺ enters the cell mainly through L-type Ca²⁺ channels and Ca²⁺ release occurs through RyR. Vasoactive agonists, by binding to their receptors, mediate Ca²⁺ release from the ER through IP3R and Ca²⁺ entry via TRPC. Intracellular Ca²⁺ maintains precise control of its own homeostasis through regulation of K⁺, Cl⁻, and Ca²⁺ release channels and Ca²⁺ pumps. Ca²⁺ regulates VSMC contraction through activation of myosin light chain kinase (MLCK) which leads to myosin light chain (MLC) phosphorylation (MLC-P). Vascular tissue injury is associated with a modulation of ion channels, pumps and Ca²⁺-binding proteins and phenotype modulation to a proliferative synthetic phenotype. Na_v voltage-dependent Na⁺ channel; K_v1.5 voltage-dependent K⁺ channel; ClC₃ voltage dependent Cl⁻ channel; VDCC voltage-dependent Ca²⁺ channel; CaM calmodulin