TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential‐dependent coupling with PTEN

Abstract

Vascular smooth muscle cells (VSMCs) play critical roles 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. Although abnormal phenotypic switching of VSMCs is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty, how control of VSMC phenotypic switching is dysregulated in pathologic conditions remains obscure. We found that inhibition of canonical transient receptor potential 6 (TRPC6) channels facilitated contractile differentiation of VSMCs through plasma membrane hyperpolarization. TRPC6‐deficient VSMCs exhibited more polarized resting membrane potentials and higher protein kinase B (Akt) activity than wild‐type VSMCs in response to TGF‐β1 stimulation. Ischemic stress elicited by oxygen‐glucose deprivation suppressed TGF‐β1‐induced hyperpolarization and VSMC differentiation, but this effect was abolished by TRPC6 deletion. TRPC6‐mediated Ca2+ influx and depolarization coordinately promoted the interaction of TRPC6 with lipid phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of Akt activation. Given the marked up‐regulation of TRPC6 observed in vascular disorders, our findings suggest that attenuation of TRPC6 channel activity in pathologic VSMCs could be a rational strategy to maintain vascular quality control by fine‐tuning of VSMC phenotypic switching.—Numaga‐Tomita, T., Shimauchi, T., Oda, S., Tanaka, T., Nishiyama, K., Nishimura, A., Birnbaumer, L., Mori, Y., Nishida, M. TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential‐dependent coupling with PTEN. FASEB J. 33, 9785–9796 (2019). http://www.fasebj.org

Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression

“…24 Many vascular diseases, such as atherosclerosis and restenosis, are closely associated with phenotypic changes from the contractile to synthetic phenotype for VSMCs. 25,26 Furthermore, a-SMA, SM myosin heavy chain, vimentin, and collagen I have been found as phenotypic markers for VSMCs. 27e29 Also, corpus cavernosum is considered as a specific vascular tissue with phenotypic transformation.…”

Transient Receptor Potential Canonical (TRPC) Channels: Then and Now

“…Notably, the TRPC6 expression level positively correlated with the increased coronary artery contractility [ 153 ]. However, an in vitro study demonstrated that TRPC6 activity promoted phenotypic switching in vascular smooth muscle cells from the contractile phenotype to the highly proliferative “synthetic” phenotype through plasma membrane potential-dependent coupling with PTEN [ 154 ]. Conversely, inhibition of TRPC6 facilitated contractile differentiation of vascular smooth muscle cells [ 154 ].…”

“…However, an in vitro study demonstrated that TRPC6 activity promoted phenotypic switching in vascular smooth muscle cells from the contractile phenotype to the highly proliferative “synthetic” phenotype through plasma membrane potential-dependent coupling with PTEN [ 154 ]. Conversely, inhibition of TRPC6 facilitated contractile differentiation of vascular smooth muscle cells [ 154 ]. The TRPC3 channel, a member of the same TRPC3/6/7 subgroup, was also found to facilitate phenotypical switch and proliferation of human smooth muscle cells from the coronary artery and aorta in vitro, and TRPC3 inhibition with Pyr3 decreased smooth vascular muscle proliferation [ 155 ].…”

Canonical transient receptor potential 6 channel deficiency promotes smooth muscle cells dedifferentiation and increased proliferation after arterial injury

“…The role of TRPC6 in the expression of contractile biomarkers may vary between the basal state and agonist-induced differentiation. A recent study by Numaga-Tomita et al 31 shows that transforming growth factor-b1-stimulated contractile differentiation and expression of SM22 is enhanced in aortic SMC harvested from TRPC6 −/− mice compared with WT mice. No difference is seen in the basal expression of SM22 between serum-starved WT and TRPC6 −/− aortic SMC, which contrasts with our findings with SMC grown in serum-supplemented medium.…”