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Testosterone promotes vascular endothelial cell migration via upregulation of ROCK-2/moesin cascade

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Abstract

Cross-sectional studies have demonstrated a reverse relationship between serum level of testosterone (T) and the incidence rate of cardiovascular disease in men, indicating that T exerts beneficial effects in cardiovascular system. However, the endothelial effects of T are poorly understood. Actin remodeling is essential for endothelial cell movement and vascular repair and this process is controlled by the actin-binding protein moesin. In the present study, we studied the effects of T on actin remodeling, moesin expression and phosphorylation, as well as cell migration in cultured human umbilical endothelial cells (hUVECs). We found that T provoked the formation of cortical actin complexes and membrane protrusions in endothelial cells. Treatment with T induced dose- and time-dependent increase of moesin expression and phosphorylation, which was inhibited by the addition of androgen receptor antagonist hydroxyflutamide (HF). Moreover, T enhanced ROCK-2 activity. The ROCK-2 inhibitor Y27632 or the transfection of ROCK-2 siRNA largely inhibited T-induced moesin expression and phosphorylation, indicating that ROCK-2 pathway is crucial for these effects. T promoted endothelial cell migration, which was inhibited by the addition of HF or Y27632. In conclusion, T induces actin cytoskeleton remodeling by regulating moesin expression and activation, resulting in enhanced endothelial cell migration. Our work adds new insights into endothelial mechanisms of T, which is relevant for its vascular actions.

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References

  1. Rosano G, Vitale C, Spoletini I, Fini M (2012) Cardiovascular health in the menopausal woman: impact of the timing of hormone replacement therapy. Climacteric 15(4):299–305

    Article  PubMed  CAS  Google Scholar 

  2. Turhan S, Tulunay C, Gulec S, Ozdol C, Kilickap M, Altin T, Gerede M, Erol C (2007) The association between androgen levels and premature coronary artery disease in men. Coron Artery Dis 18(3):159–162

    Article  PubMed  Google Scholar 

  3. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N (2007) Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation 116(23):2694–2701

    Article  PubMed  CAS  Google Scholar 

  4. Phillips GB, Pinkernell BH, Jing TY (1994) The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb 14(5):701–706

    Article  PubMed  CAS  Google Scholar 

  5. Feletou M, Vanhoutte PM (2006) Endothelial dysfunction: a multifaceted disorder (The wiggers award lecture). Am J Physiol Heart Circ Physiol 291(3):H985–H1002

    Article  PubMed  CAS  Google Scholar 

  6. Woywodt A, Bahlmann FH, De Groot K, Haller H, Haubitz M (2002) Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer. Nephrol Dial Transplant 17(10):1728–1730

    Article  PubMed  Google Scholar 

  7. Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115(10):1285–1295

    PubMed  Google Scholar 

  8. Simoncini T, Scorticati C, Mannella P, Fadiel A, Giretti MS, Fu XD, Baldacci C, Garibaldi S, Caruso A, Fornari L et al (2006) Estrogen receptor alpha interacts with Galpha13 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway. Mol Endocrinol 20(8):1756–1771

    Article  PubMed  CAS  Google Scholar 

  9. Fu XD, Flamini M, Sanchez AM, Goglia L, Giretti MS, Genazzani AR, Simoncini T (2008) Progestogens regulate endothelial actin cytoskeleton and cell movement via the actin-binding protein moesin. Mol Hum Reprod 14(4):225–234

    Article  PubMed  CAS  Google Scholar 

  10. Craige SM, Chen K, Pei Y, Li C, Huang X, Chen C, Shibata R, Sato K, Walsh K, Keaney JF Jr (2011) NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. Circulation 124(6):731–740

    Article  PubMed  CAS  Google Scholar 

  11. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C et al (2001) Testosterone dose–response relationships in healthy young men. Am J Physiol Endocrinol Metab 281(6):E1172–E1181

    PubMed  CAS  Google Scholar 

  12. Berryman M, Franck Z, Bretscher A (1993) Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci 105(Pt 4):1025–1043

    PubMed  CAS  Google Scholar 

  13. He M, Cheng Y, Li W, Liu Q, Liu J, Huang J, Fu X (2010) Vascular endothelial growth factor C promotes cervical cancer metastasis via up-regulation and activation of RhoA/ROCK-2/moesin cascade. BMC Cancer 10:170

    Article  PubMed  Google Scholar 

  14. Louvet-Vallee S (2000) ERM proteins: from cellular architecture to cell signaling. Biol Cell 92(5):305–316

    Article  PubMed  CAS  Google Scholar 

  15. Polesello C, Payre F (2004) Small is beautiful: what flies tell us about ERM protein function in development. Trends Cell Biol 14(6):294–302

    Article  PubMed  CAS  Google Scholar 

  16. Giannone G, Dubin-Thaler BJ, Dobereiner HG, Kieffer N, Bresnick AR, Sheetz MP (2004) Periodic lamellipodial contractions correlate with rearward actin waves. Cell 116(3):431–443

    Article  PubMed  CAS  Google Scholar 

  17. Chen Y, Fu L, Han Y, Teng Y, Sun J, Xie R, Cao J (2012) Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF. Eur J Pharmacol 684(1–3):116–124

    Article  PubMed  CAS  Google Scholar 

  18. Cinar B, Koeneman KS, Edlund M, Prins GS, Zhau HE, Chung LW (2001) Androgen receptor mediates the reduced tumor growth, enhanced androgen responsiveness, and selected target gene transactivation in a human prostate cancer cell line. Cancer Res 61(19):7310–7317

    PubMed  CAS  Google Scholar 

  19. Hammes SR, Levin ER (2011) Minireview: recent advances in extranuclear steroid receptor actions. Endocrinology 152(12):4489–4495

    Article  PubMed  CAS  Google Scholar 

  20. Menager C, Vassy J, Doliger C, Legrand Y, Karniguian A (1999) Subcellular localization of RhoA and ezrin at membrane ruffles of human endothelial cells: differential role of collagen and fibronectin. Exp Cell Res 249(2):221–230

    Article  PubMed  CAS  Google Scholar 

  21. Vaiskunaite R, Adarichev V, Furthmayr H, Kozasa T, Gudkov A, Voyno-Yasenetskaya TA (2000) Conformational activation of radixin by G13 protein alpha subunit. J Biol Chem 275(34):26206–26212

    Article  PubMed  CAS  Google Scholar 

  22. Chavalmane AK, Comeglio P, Morelli A, Filippi S, Fibbi B, Vignozzi L, Sarchielli E, Marchetta M, Failli P, Sandner P et al (2010) Sex steroid receptors in male human bladder: expression and biological function. J Sex Med 7(8):2698–2713

    Article  PubMed  CAS  Google Scholar 

  23. Vignozzi L, Morelli A, Filippi S, Ambrosini S, Mancina R, Luconi M, Mungai S, Vannelli GB, Zhang XH, Forti G et al (2007) Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med 4(3):620–630 discussion 631–632

    Article  PubMed  CAS  Google Scholar 

  24. Liao CH, Lin FY, Wu YN, Chiang HS (2012) Androgens inhibit tumor necrosis factor-alpha-induced cell adhesion and promote tube formation of human coronary artery endothelial cells. Steroids 77(7):756–764

    Article  PubMed  CAS  Google Scholar 

  25. Tharp DL, Masseau I, Ivey J, Ganjam VK, Bowles DK (2009) Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine. Cardiovasc Res 82(1):152–160

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation (To X.D. Fu., No. 81270669) and by the foundation of Guangzhou Pearl River Science New Star (To X.D. Fu., No: 2011J2200094) and by the Natural Science Foundation of Guangdong Province (To X.D.Fu., No: S2013010016548).

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Authors and Affiliations

  1. Department of Physiology, Guiling Medical College, Guiling City, 541004, Guangxi Province, China

    Weiyong Liao, Wenjun Huang, Yanhong Guo & Min Xin

  2. Department of Physiology, School of basic science, Guangzhou Medical University, Guangzhou City, 510182, Guangdong Province, China

    Xiaodong Fu

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  1. Weiyong Liao
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  2. Wenjun Huang
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  3. Yanhong Guo
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  4. Min Xin
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Correspondence to Xiaodong Fu.

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Liao, W., Huang, W., Guo, Y. et al. Testosterone promotes vascular endothelial cell migration via upregulation of ROCK-2/moesin cascade. Mol Biol Rep 40, 6729–6735 (2013). https://doi.org/10.1007/s11033-013-2788-8

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  • DOI: https://doi.org/10.1007/s11033-013-2788-8

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