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 voltageoperated 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.

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

“…However the mode of contraction, phasic or tonic, is determined by the type of cytosolic Ca 2+ cycling. Different types of calcium cycling were observed in synthetic and contractile tonic or phasic VSMCs, in accordance with differential expression of calcium handling proteins [59,60,66].…”

“…Transition of contractile VSMCs towards a proliferating/migratory/inflammatory phenotype is one of the initial mechanisms leading to pathological vascular remodeling 7 [58,60]. Culturing VSMCs in vitro mimics this progression, as primary cultures rapidly lose differentiation markers and exhibit a synthetic phenotype [60].…”

“…The hallmark of synthetic status of VSMCs is a lack of functional proteins entity associated with the contractile response [60]; we refer to voltage activated L-type calcium channels (LTCC), SR calcium release channel RyR and "fast" isoform of SR calcium pump SERCA2a (Figure 3). In line with this, large conductance K + channels (BKCa), which are involved in negative feedback regulation of LTCC activity through plasma membrane hyperpolarization, are also downregulated in synthetic VSMC [67,68].…”

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

“…It is widely accepted that while VSMCs in the healthy vessel wall are contractile, dispersed cells in culture rapidly modulate from a contractile differentiated phenotype to a synthetic phenotype (47). This phenotypic switch has been shown to take place and contribute to vascular disease states (e.g., atherosclerosis, hypertensive microvessels, restenosis) (48). A time-dependent decrease in GIPR expression was found instead when smooth muscle cells were cultured in differentiating medium (Fig.…”

Emerging roles of Orai3 in pathophysiology

“…75,76 VSMCs primary function is to maintain blood pressure and vascular tone. Upon mechanical injury, diet-induced injury or insults from exposure to chronic high blood pressure or inflammatory molecules, VSMCs switch to a highly proliferative and migratory phenotype, called synthetic phenotype.…”