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

Numaga‐Tomita, Takuro; Shimauchi, Takashi; Oda, Sayaka; Tanaka, Tomohiro; Nishiyama, Kazuhiro; Nishimura, Akiyoshi; Birnbaumer, Lutz; Mori, Yasuo; Nishida, Motohiro

doi:10.1096/fj.201802811r

Cited by 32 publications

(33 citation statements)

References 41 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Introduction: Cavernosal nerve (CN) injury is commonly caused by radical prostatectomy surgery, and it might directly lead to erectile dysfunction (ED). Currently, the role of mitogen-activated protein kinase (MAPK) family proteins in phenotypic transformation of corpus cavernosum smooth muscle cell (CCSMC) after CNs injury is poorly understood. Aim: To investigate the role of p38 MAPK in hypoxia-induced phenotypic transformation of CCSMCs after CN injury. Methods: In total, 20 SpragueeDawley rats (male and 8 weeks of age) were randomly divided into 2 groups, including a sham group and CNCI group. In the sham group, rats were sham-operated by identifying 2 CNs without causing direct damage to the CNs. In the CNCI group, rats were subjected to bilateral CN crush injury. CCSMCs were isolated from the normal corpus cavernosum tissues of the SpragueeDawley rat and then cultured in 21% or 1% O 2 concentration context for 48 hours. Main Outcome Measures: Intracavernous pressure/mean arterial pressure were analyzed to measure erectile response. The impact of hypoxia on penile pathology, as well as the expression of extracellular signal-regulated kinases, the c-Jun NH2-terminal kinase, and p38 MAPK, were analyzed. Results: Compared with the sham group, the intracavernous pressure/mean arterial pressure rate and a-smooth muscle actin expression of CNCI group were decreased significantly (P ¼ .0001; P ¼ .016, respectively), but vimentin expression was significantly increased (P ¼ .023). Phosphorylated p38 level in CNCI group was decreased significantly (P ¼ .017; sham: 0.17 ± 0.005; CNCI: 0.14 ± 0.02). The CCSMCs in the normoxia group were long fusiform, whereas the morphology of CCSMCs in the hypoxia group became hypertrophic. After hypoxia for 48 hours, the expression of a-smooth muscle actin and phosphorylated p38 MAPK was decreased significantly (P ¼ .01; P ¼ .024, normoxia: 0.66 ± 0.18, hypoxia: 0.26 ± 0.08, respectively), and the expression of hypoxia-inducible factor-1a and collagen I was increased significantly in hypoxia group (P ¼ .04; P ¼ .012, respectively). Conclusions: Hypoxia induced the phenotypic transformation of CCSMCs after CNCI might be associated with the downregulation of phosphorylated p38 MAPK. Chen S, Huang X, Kong X, et al. Hypoxia-Induced

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…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 ].…”

Section: Physiological and Pathological Functions Of Trpcs Revealementioning

confidence: 99%

“…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 ].…”

Section: Physiological and Pathological Functions Of Trpcs Revealementioning

confidence: 99%

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

Chen

Sooch

Demaree

et al. 2020

Cells

113

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Twenty-five years ago, the first mammalian Transient Receptor Potential Canonical (TRPC) channel was cloned, opening the vast horizon of the TRPC field. Today, we know that there are seven TRPC channels (TRPC1–7). TRPCs exhibit the highest protein sequence similarity to the Drosophila melanogaster TRP channels. Similar to Drosophila TRPs, TRPCs are localized to the plasma membrane and are activated in a G-protein-coupled receptor-phospholipase C-dependent manner. TRPCs may also be stimulated in a store-operated manner, via receptor tyrosine kinases, or by lysophospholipids, hypoosmotic solutions, and mechanical stimuli. Activated TRPCs allow the influx of Ca2+ and monovalent alkali cations into the cytosol of cells, leading to cell depolarization and rising intracellular Ca2+ concentration. TRPCs are involved in the continually growing number of cell functions. Furthermore, mutations in the TRPC6 gene are associated with hereditary diseases, such as focal segmental glomerulosclerosis. The most important recent breakthrough in TRPC research was the solving of cryo-EM structures of TRPC3, TRPC4, TRPC5, and TRPC6. These structural data shed light on the molecular mechanisms underlying TRPCs’ functional properties and propelled the development of new modulators of the channels. This review provides a historical overview of the major advances in the TRPC field focusing on the role of gene knockouts and pharmacological tools.

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“…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.…”

Section: Discussionmentioning

confidence: 96%

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

Smith

Putta

Driscoll

et al. 2020

JVS-Vascular Science

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Objective: Previous studies showed the benefit of canonical transient receptor potential 6 (TRPC6) channel deficiency in promoting endothelial healing of arterial injuries in hypercholesterolemic animals. Long-term studies utilizing a carotid wire-injury model were undertaken in wild-type (WT) and TRPC6 −/− mice to determine the effects of TRPC6 on phenotypic modulation of vascular smooth muscle cells (SMC) and neointimal hyperplasia. We hypothesized that TRPC6 was essential in the maintenance or reexpression of a differentiated SMC phenotype and minimized luminal stenosis following arterial injury. Methods: The common carotid arteries (CCA) of WT and TRPC6 −/− mice were evaluated at baseline and 4 weeks after wire injury. At baseline, CCA of TRPC6 −/− mice had reduced staining of MYH11 and SM22, fewer elastin lamina, luminal dilation, and wall thinning. After carotid wire injury, TRPC6 −/− mice developed significantly more pronounced luminal stenosis compared with WT mice. Injured TRPC6 −/− CCA demonstrated increased medial/intimal cell number and active cell proliferation when compared with WT CCA. Immunohistochemistry suggested that expression of contractile biomarkers in medial SMC were essentially at baseline levels in WT CCA at 28 days after wire injury. By contrast, at 28 days after injury medial SMC from TRPC6 −/− CCA showed a significant decrease in the expression of contractile biomarkers relative to baseline levels. To assess the role of TRPC6 in systemic arterial SMC phenotype modulation, SMC were harvested from thoracic aortae of WT and TRPC6 −/− mice and were characterized. TRPC6 −/− SMC showed enhanced proliferation and migration in response to serum stimulation. Expression of contractile phenotype biomarkers, MYH11 and SM22, was attenuated in TRPC6 −/− SMC. siRNA-mediated TRPC6 deficiency inhibited contractile biomarker expression in a mouse SMC line. Conclusions: These results suggest that TRPC6 contributes to the restoration or maintenance of arterial SMC contractile phenotype following injury. Understanding the role of TRPC6 in phenotypic modulation may lead to mechanism-based therapies for attenuation of IH.

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

Cited by 32 publications

References 41 publications

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

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

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

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

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