J Lipid Atheroscler.  2020 Jan;9(1):124-139. 10.12997/jla.2020.9.1.124.

Canonical Transient Receptor Potential Channels and Vascular Smooth Muscle Cell Plasticity

• Nishida M
• Tanaka T
• Mangmool S
• Nishiyama
• Nishimura

• KMID: 2470805
• DOI: http://doi.org/10.12997/jla.2020.9.1.124

Abstract

Vascular smooth muscle cells (VSMCs) play a pivotal role in the stability and tonic regulation of vascular homeostasis. VSMCs can switch back and forth between highly proliferative (synthetic) and fully differentiated (contractile) phenotypes in response to changes in the vessel environment. Abnormal phenotypic switching of VSMCs is a distinctive characteristic of vascular disorders, including atherosclerosis, pulmonary hypertension, stroke, and peripheral artery disease; however, how the control of VSMC phenotypic switching is dysregulated under pathological conditions remains obscure. Canonical transient receptor potential (TRPC) channels have attracted attention as a key regulator of pathological phenotype switching in VSMCs. Several TRPC subfamily member proteins"”especially TRPC1 and TRPC6"”are upregulated in pathological VSMCs, and pharmacological inhibition of TRPC channel activity has been reported to improve hypertensive vascular remodeling in rodents. This review summarizes the current understanding of the role of TRPC channels in cardiovascular plasticity, including our recent finding that TRPC6 participates in aberrant VSMC phenotype switching under ischemic conditions, and discusses the therapeutic potential of TRPC channels.

Keyword

Transient receptor potential channel; Phenotype switching; Remodeling; Excitation-transcription coupling

MeSH Terms

Atherosclerosis
Cell Plasticity*
Homeostasis
Hypertension, Pulmonary
Muscle, Smooth, Vascular*
Peripheral Arterial Disease
Phenotype
Plastics
Rodentia
Stroke
Transient Receptor Potential Channels*
Vascular Remodeling
Plastics
Transient Receptor Potential Channels

Figure

• 

  Fig. 1 Characteristics of synthetic and proliferative VSMCs. Contractile VSMCs abundantly express voltage-dependent LTCC, which predominantly mediate Ca2+-dependent contraction through a MLC phosphorylation-dependent pathway (excitation-contraction coupling). In contrast, synthetic VSMCs abundantly expresses receptor-activated TRPC channels, which mediate GPCR-stimulated gene expression through the activation or inactivation of several transcriptional factors (excitation-transcription coupling). VSMC, vascular smooth muscle cell; LTCC, L-type Ca2+ channels; MLC, myosin light chain; TRPC, canonical transient receptor potential; GPCR, G protein-coupled receptor; α-SMA, α-smooth muscle actin; TGF-β, transforming growth factor beta; PDGF, platelet-derived growth factor; CREB, cAMP response element binding protein; MLCP, myosin light chain phosphatase; MRTF, myocardin-related transcription factor; NFAT, nuclear factor of activated T cells; ROCK, Rho kinase; SRF, serum response factor.

• 

  Fig. 2 Physiological and pathophysiological significance of TRPC6 in VSMC phenotype switching. Increased TRPC6 channel activity plays a critical role in determining the VSMC phenotype. Once VSMCs are exposed to metabolic stresses, such as hypoxia, nutrient deficiency and glucose deprivation, TRPC6 channel activity is increased and TRPC6-mediated cation influx suppresses VSMC switching from the synthetic to contractile phenotype upon TGF-β stimulation through PTEN-dependent reduction of Akt activity. VSMC, vascular smooth muscle cell; TRPC, canonical transient receptor potential; TGF-β, transforming growth factor beta; PTEN, phosphatase and tensin homologue deleted from chromosome 10.

• 

  Fig. 3 Several TRPC3/C6 inhibitors and their pharmacological effects on the cardiovascular system. TRPC, canonical transient receptor potential; PAD, peripheral arterial disease; PAH, pulmonary arterial hypertension; Dox, doxorubicin.

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