Skip to main content
SpringerLink
Log in

TSH stimulates the proliferation of vascular smooth muscle cells

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Subclinical hypothyroidism (SCH) was reported to be associated with atherosclerosis (AS) in recent studies. Thyroid hormone levels are normal in patients with SCH, but the levels of thyroid-stimulating hormone (TSH) are increased. Thyroid-stimulating hormone receptor (TSHR) in extra-thyroidal tissues plays a pathophysiological role in these conditions. Our previous results demonstrated that TSHR was functional in hepatocytes and revealed elevated total cholesterol levels in the serum, which were an independent risk factor for AS. TSHR is expressed in vascular smooth muscle cells (VSMCs), and VSMC proliferation plays an important role in the development of AS. Cell proliferation was measured by the MTT assay. Intracellular cyclic AMP (cAMP) was measured using a cAMP ELISA kit. Cells were analyzed using a flow cytometer to determine the cell-cycle phase of each cell. For the purpose of detecting cyclin A and cyclin D, immunohistochemical staining and western blots were performed. Real-time PCR was used to assess the VSMC phenotypes. TSH increased cell progression into the G2/M phases and induced VSMC proliferation; thus, functional TSHR was present on VSMCs. Furthermore, the expression of cyclin D1 and cyclin A was increased. In addition, the results indicated that VSMCs undergo a phenotypic transformation from a contractile state to a synthetic state after treatment with different concentrations of TSH. Elevated TSH can promote VSMC proliferation through the cAMP-dependent pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. G.J. Kahaly, W.H. Dillmann, Thyroid hormone action in the heart. Endocr. Rev. 26(5), 704–728 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. T. Ichiki, Thyroid hormone and atherosclerosis. Vascul. Pharmacol. 52, 151–156 (2010)

    Article  CAS  PubMed  Google Scholar 

  3. I. Klein, S. Danzi, Thyroid disease and the heart. Circulation 116, 1725–1735 (2007)

    Article  PubMed  Google Scholar 

  4. G. Da Xiang, L.W. Xiang, H.L. He, L.S. Zhao, Post prandial lipaemia suppresses endothelium-dependent arterial dilation in patients with hypothyroidism. Endocrine 42, 391–398 (2012)

    Article  CAS  PubMed  Google Scholar 

  5. E. Cebeci, F.A. Oner, M. Usta, S. Yurdakul, M. Erguney, Evaluation of oxidative stress, the activities of paraoxonase and arylesterase in patients with subclinic hypothyroidism. Acta Biomed. 82, 214–222 (2011)

    PubMed  Google Scholar 

  6. L.B. Yang, D.Q. Jiang, W.B. Qi, T. Zhang, Y.L. Feng, L. Gao, J. Zhao, Subclinical hyperthyroidism and the risk of cardiovascular events and all-cause mortality: an updated meta-analysis of cohort studies. Eur. J. Endocrinol. 167, 75–84 (2012)

    Article  CAS  PubMed  Google Scholar 

  7. G. Csaba, E. Pallinger, Thyrotropic hormone (TSH) regulation of triiodothyronine (T3) concentration in immune cells. Inflamm. Res. 58, 151–154 (2009)

    Article  CAS  PubMed  Google Scholar 

  8. M. Nannipieri, F. Cecchetti, M. Anselmino, S. Camastra, P. Niccolini, M. Lamacchia, M. Rossi, G. Iervasi, E. Ferrannini, Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: effects of weight loss. Int. J. Obes. 33, 1001–1006 (2009)

    Article  CAS  Google Scholar 

  9. K.A. Heemstra, W.M. van der Deure, R.P. Peeters, N.A. Hamdy, M.P. Stokkel, E.P. Corssmit, J.A. Romijn, T.J. Visser, J.W. Smit, Thyroid hormone independent associations between serum TSH levels and indicators of bone turnover in cured patients with differentiated thyroid carcinoma. Eur. J. Endocrinol. 159, 69–76 (2008)

    Article  CAS  PubMed  Google Scholar 

  10. W. Zhang, L.M. Tian, Y. Han, H.Y. Ma, L.C. Wang, J. Guo, L. Gao, J.J. Zhao, Presence of thyrotropin receptor in hepatocytes: not a case of illegitimate transcription. J. Cell. Mol. Med. 13, 4636–4642 (2009)

    Article  CAS  PubMed  Google Scholar 

  11. L. Tian, Y. Song, M. Xing, W. Zhang, G. Ning, X. Li, C. Yu, C. Qin, J. Liu, X. Tian, X. Sun, R. Fu, L. Zhang, X. Zhang, Y. Lu, J. Zou, L. Wang, Q. Guan, L. Gao, J.J. Zhao, A novel role for thyroid-stimulating hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway. Hepatology 52(4), 1401–1409 (2010)

    Article  CAS  PubMed  Google Scholar 

  12. D.F. Sellitti, D. Dennison, T. Akamizu, S.Q. Doi, L.D. Kohn, H. Koshiyama, Thyrotropin regulation of cyclic adenosinemonophosphate production in human coronary artery smooth muscle cells. Thyroid 10, 219–225 (2000)

    Article  CAS  PubMed  Google Scholar 

  13. A.R. Yoo, S.H. Koh, G.W. Cho, S.H. Kim, Inhibitory effects of cilostazol on proliferation of vascular smooth muscle cells (VSMCs) through suppression of the ERK1/2 pathway. J. Atheroscler. Thromb. 17, 1009–1018 (2010)

    Article  CAS  PubMed  Google Scholar 

  14. G.J. Song, N. Fiaschi-Taesch, A. Bisello, Endogenous parathyroid hormone-related protein regulates the expression of PTH type 1 receptor and proliferation of vascular smooth muscle cells. Mol. Endocrinol. (Baltimore, Md.) 23, 1681–1690 (2009)

    Article  CAS  Google Scholar 

  15. K. Yokouchi, Y. Numaguchi, R. Kubota, M. Ishii, H. Imai, R. Murakami, Y. Ogawa, T. Kondo, K. Okumura, D.E. Ingber, T. Murohara, l-Caldesmon regulates proliferation and migration of vascular smooth muscle cells and inhibits neointimal formation after angioplasty. Arterioscler. Thromb. Vasc. Biol. 26(10), 2231–2237 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. R. Zargham, Preventing restenosis after angioplasty: a multistage approach. Clin. Sci. (Lond). 114(4), 257–264 (2008)

    Article  PubMed  Google Scholar 

  17. Qifeng. Jiang, Renjian. Huang, Shaoxi. Cai, C.L. Wang, Caldesmon regulates the motility of vascular smooth muscle cells by modulating the actin cytoskeleton stability. J. Biomed. Sci. 17, 6 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  18. D.N. Atochin, P.L. Huang, Endothelial nitric oxide synthase transgenic models of endothelial dysfunction. Pflugers Arch. 460(6), 965–974 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. R. Napoli, V. Apuzzi, G. Bosso, C. D’Anna, A. De Sena, C. Pirozzi, A. Marano, G.A. Lupoli, G. Cudemo, U. Oliviero, Recombinant human thyrotropin enhances endothelial-mediated vasodilation of conduit arteries. J. Clin. Endocrinol. Metab. 94(3), 1012–1016 (2009)

    Article  CAS  PubMed  Google Scholar 

  20. R. Napoli, B. Biondi, V. Guardasole, C. D’Anna, A. De Sena, C. Pirozzi, D. Terracciano, C. Mazzarella, M. Matarazzo, L. Sacca, Enhancement of vascular endothelial function by recombinant human thyrotropin. J. Clin. Endocrinol. Metab. 93(5), 1959–1963 (2008)

    Article  CAS  PubMed  Google Scholar 

  21. A. Haribabu, V.S. Reddy, C. Pallavi, A.R. Bitla, A. Sachan, P. Pullaiah, V. Suresh, P.V. Rao, M.M. Suchitra, Evaluation of protein oxidation and its association with lipid peroxidation and thyrotropin levels in overt and subclinical hypothyroidism. Endocrine 44, 152–157 (2013)

    Article  CAS  PubMed  Google Scholar 

  22. P. Agretti, G. De Marco, M. De Servi, C. Marcocci, P. Vitti, A. Pinchera, M. Tonacchera, Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation. Eur. J. Endocrinol. 152, 777–784 (2005)

    Article  CAS  PubMed  Google Scholar 

  23. T.T. Antunes, A. Gagnon, A. Bell, A. Sorisky, Thyroid-stimulating hormone stimulates interleukin-6 release from 3T3-L1 adipocytes through a cAMP-protein kinase A pathway. Obes. Res. 13, 2066–2071 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. H. Guo, N. Makarova, Y. Cheng, E. Shuyu, R.R. Ji, C. Zhang, P. Farrarc, G. Tigyia, The early- and late stages in phenotypic modulation of vascular smooth muscle cells: differential roles for lysophosphatidic acid. Biochim. Biophys. Acta 1781(9), 571–581 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. E.M. Rzucidlo, Signaling pathways regulating vascular smooth muscle cell differentiation. Vascular 17(Suppl 1), S15–S20 (2009)

    Article  PubMed  Google Scholar 

  26. R.E. Clempus, D. Sorescu, A.E. Dikalova, L. Pounkova, P. Jo, G.P. Sorescu, B. Lassègue, K.K. Griendling, Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler. Thromb. Vasc. Biol. 27(1), 42–48 (2007)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. C.L. Wang, Caldesmon and the regulation of cytoskeletal functions. Adv. Exp. Med. Biol. 644, 250–272 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. E.S. Park, J.M. Yoo, Y. Lim, M. Tudev, H.S. Yoo, J.T. Hong, Y.P. Yun, Inhibitory effects of docetaxel on platelet-derived growth factor (PDGF)-BB-induced proliferation of vascular smooth muscle cells through blocking PDGF-receptor beta phosphorylation. J. Pharmacol. Sci. 116(2), 204–213 (2011)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the teachers in the central laboratory of the first hospital of Lanzhou University for their excellent technical assistance. This research was funded by grants from the National Natural Science Foundation of China (81160100) and the Health Planning Project of Gansu Province (GSWST2011-01).

Author information

Authors and Affiliations

  1. Department of Endocrinology, Gansu Provincial Hospital, 204 Dong Gang West Road, Lanzhou, 730000, China

    Limin Tian, Jing Liu, Qian Guo & Luyan Zhang

  2. Graduate School, Ningxia Medical University, No. 1160 Shengli Str., Yinchuan, 750004, Ningxia, China

    Jing Ni

  3. Department of General Surgery, Gansu Provincial Hospital, 204 Dong Gang West Road, Lanzhou, 730000, China

    Tiankang Guo

  4. Department of Pathobiology, Gansu Provincial Hospital, 204 Dong Gang West Road, Lanzhou, 730000, China

    Yamei Dang

Authors
  1. Limin Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tiankang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yamei Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tiankang Guo.

Additional information

Limin Tian and Jing Ni contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tian, L., Ni, J., Guo, T. et al. TSH stimulates the proliferation of vascular smooth muscle cells. Endocrine 46, 651–658 (2014). https://doi.org/10.1007/s12020-013-0135-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-013-0135-4

Keywords

Search

Navigation