Phenotypic transformation from adventitial fibroblasts (AFs) to myofibroblasts (MFs) is critical for vascular remodeling. Septin 2 was found to be downregulated during the differentiation of AFs to MFs induced by angiotensin II (Ang II); however, the role of septin 2 in this process is still unknown. In this study, we investigate whether septin 2 contributes to the adventitial MF phenotypic modulation caused by Ang II. The decreased level of septin 2 and the increased expression of α-smooth muscle actin (α-SMA), a marker of MFs, were readily observed in Ang II-stimulated MF differentiation. After gene transfer of septin 2, the expression of α-SMA was markedly decreased and the MF migration response to Ang II was inhibited. Furthermore, the inhibition of RhoA, another molecule involved in MF phenotypic modulation, decreased the motility of MFs and the expression of septin 2 triggered in Ang II. Finally, transfection of septin 2 rescued the level of acetyl-α-tubulin in MFs. These findings demonstrate that, as a downstream molecule of RhoA, septin 2 blunted the responses of AFs to Ang II by protecting α-tubulin acetylation, which suggests that septin 2 may serve as a potential therapeutic target for vascular injury.

1.
Bots ML, Dijk JM, Oren A, Grobbee DE: Carotid intima-media thickness, arterial stiffness and risk of cardiovascular disease: current evidence. J Hypertens 2002;20:2317-2325.
2.
Laurent S: Arterial wall hypertrophy and stiffness in essential hypertensive patients. Hypertension 1995;26:355-362.
3.
Sartore S, Chiavegato A, Faggin E, Franch R, Puato M, Ausoni S, Pauletto P: Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ Res 2001;89:1111-1121.
4.
Li G, Chen SJ, Oparil S, Chen YF, Thompson JA: Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation 2000;101:1362-1365.
5.
Shi Y, Pieniek M, Fard A, O'Brien J, Mannion JD, Zalewski A: Adventitial remodeling after coronary arterial injury. Circulation 1996;93:340-348.
6.
Siow RC, Mallawaarachchi CM, Weissberg PL: Migration of adventitial myofibroblasts following vascular balloon injury: insights from in vivo gene transfer to rat carotid arteries. Cardiovasc Res 2003;59:212-221.
7.
Chen J, Wu J, Li L, Zou YZ, Zhu DL, Gao PJ: Effect of an acute mechanical stimulus on aortic structure in the transverse aortic constriction mouse model. Clin Exp Pharmacol Physiol 2011;38:570-576.
8.
Eberth JF, Gresham VC, Reddy AK, Popovic N, Wilson E, Humphrey JD: Importance of pulsatility in hypertensive carotid artery growth and remodeling. J Hypertens 2009;27:2010-2021.
9.
Li Y, Jiang H, Ruan C, Zhong J, Gao P, Zhu D, Niu W, Guo S: The interaction of transient receptor potential melastatin 7 with macrophages promotes vascular adventitial remodeling in transverse aortic constriction rats. Hypertens Res 2014;37:35-42.
10.
Li YH, Hsieh CY, Wang DL, Chung HC, Liu SL, Chao TH, Shi GY, Wu HL: Remodeling of carotid arteries is associated with increased expression of thrombomodulin in a mouse transverse aortic constriction model. Thromb Haemost 2007;97:658-664.
11.
Dzau VJ: Theodore Cooper Lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001;37:1047-1052.
12.
Shen WL, Gao PJ, Che ZQ, Ji KD, Yin M, Yan C, Berk BC, Zhu DL: NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation. Biochem Biophys Res Commun 2006;339:337-343.
13.
Li L, Zhu DL, Shen WL, Gao PJ: Increased migration of vascular adventitial fibroblasts from spontaneously hypertensive rats. Hypertens Res 2006;29:95-103.
14.
Kim DK, Huh JE, Lee SH, Hong KP, Park JE, Seo JD, Lee WR: Angiotensin II stimulates proliferation of adventitial fibroblasts cultured from rat aortic explants. J Korean Med Sci 1999;14:487-496.
15.
Kinoshita M, Kumar S, Mizoguchi A, Ide C, Kinoshita A, Haraguchi T, Hiraoka Y, Noda M: Nedd5, a mammalian septin, is a novel cytoskeletal component interacting with actin-based structures. Genes Dev 1997;11:1535-1547.
16.
Schmidt K, Nichols BJ: Functional interdependence between septin and actin cytoskeleton. BMC Cell Biol 2004;5:43.
17.
Gera N, Yang A, Holtzman TS, Lee SX, Wong ET, Swanson KD: Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS One 2015;10: e0125269.
18.
Sakai K, Kurimoto M, Tsugu A, Hubbard SL, Trimble WS, Rutka JT: Expression of Nedd5, a mammalian septin, in human brain tumors. J Neurooncol 2002;57:169-177.
19.
Swanson KD, Lok E, Wong ET: An overview of alternating electric fields therapy (novoTTF therapy) for the treatment of malignant glioma. Curr Neurol Neurosci Rep 2016;16:8.
20.
Cao LQ, Shao ZL, Liang HH, Zhang DW, Yang XW, Jiang XF, Xue P: Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits hepatoma cell growth via downregulation of SEPT2 expression. Cancer Lett 2015;359:127-135.
21.
Marcus EA, Tokhtaeva E, Turdikulova S, Capri J, Whitelegge JP, Scott DR, Sachs G, Berditchevski F, Vagin O: Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells. Biochem J 2016;473:1703-1718.
22.
Sidhaye VK, Chau E, Breysse PN, King LS: Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions. Am J Respir Cell Mol Biol 2011;45:120-126.
23.
Sidhaye VK, Schweitzer KS, Caterina MJ, Shimoda L, King LS: Shear stress regulates aquaporin-5 and airway epithelial barrier function. Proc Natl Acad Sci USA 2008;105:3345-3350.
24.
Ostergaard M, Hansen GA, Vorum H, Honore B: Proteomic profiling of fibroblasts reveals a modulating effect of extracellular calumenin on the organization of the actin cytoskeleton. Proteomics 2006;6:3509-3519.
25.
Guo SJ, Wu LY, Wei J, Gao PJ, Zhu DL: Research on proteins associated to differentiation of vascular adventitial myofibroblasts. Acta Chimica Sinica 2007;65:1504-1510.
26.
Gao PJ, Li Y, Sun AJ, Liu JJ, Ji KD, Zhang YZ, Sun WL, Marche P, Zhu DL: Differentiation of vascular myofibroblasts induced by transforming growth factor-β1 requires the involvement of protein kinase C α. J Mol Cell Cardiol 2003;35:1105-1112.
27.
Zhou HY, Chen WD, Zhu DL, Wu LY, Zhang J, Han WQ, Li JD, Yan C, Gao PJ: The PDE1A-PKCα signaling pathway is involved in the upregulation of α-smooth muscle actin by TGF-β1 in adventitial fibroblasts. J Vasc Res 2010;47:9-15.
28.
Zhu DL, Herembert T, Marche P: Increased proliferation of adventitial fibroblasts from spontaneously hypertensive rat aorta. J Hypertens 1991;9:1161-1168.
29.
Chen W, Chu Y, Zhu D, Yan C, Liu J, Ji K, Gao P: Perivascular gene transfer of dominant-negative N19RhoA attenuates neointimal formation via inhibition of TGF-β1-Smad2 signaling in rats after carotid artery balloon injury. Biochem Biophys Res Commun 2009;389:217-223.
30.
Chen WD, Chu YF, Liu JJ, Hong MN, Gao PJ: RhoA-Rho kinase signaling pathway mediates adventitial fibroblasts differentiation to myofibroblasts induced by TGF-β1. Sheng Li Xue Bao 2013;65:113-121.
31.
Strauss BH, Rabinovitch M: Adventitial fibroblasts: defining a role in vessel wall remodeling. Am J Respir Cell Mol Biol 2000;22:1-3.
32.
Wallner K, Sharifi BG, Shah PK, Noguchi S, DeLeon H, Wilcox JN: Adventitial remodeling after angioplasty is associated with expression of tenascin mRNA by adventitial myofibroblasts. J Am Coll Cardiol 2001;37:655-661.
33.
Zhang J, Tang SJ, Wang XK, Liang XQ, Sun WJ: An observation of the effects of the truncated septin2 on mouse epidermal cell and fibroblast. Zhonghua Zheng Xing Wai Ke Za Zhi 2007;23:147-150.
34.
Schofield AV, Steel R, Bernard O: Rho-associated coiled-coil kinase (ROCK) protein controls microtubule dynamics in a novel signaling pathway that regulates cell migration. J Biol Chem 2012;287:43620-43629.
35.
Chitaley K, Webb RC: Microtubule depolymerization facilitates contraction of vascular smooth muscle via increased activation of RhoA/Rho-kinase. Med Hypotheses 2001;56:381-385.
36.
Aspenstrom P, Fransson A, Saras J: Rho GTPases have diverse effects on the organization of the actin filament system. Biochem J 2004;377:327-337.
37.
Belletti B, Pellizzari I, Berton S, Fabris L, Wolf K, Lovat F, Schiappacassi M, D'Andrea S, Nicoloso MS, Lovisa S, Sonego M, Defilippi P, Vecchione A, Colombatti A, Friedl P, Baldassarre G: P27kip1 controls cell morphology and motility by regulating microtubule-dependent lipid raft recycling. Mol Cell Biol 2010;30:2229-2240.
38.
Destaing O, Saltel F, Gilquin B, Chabadel A, Khochbin S, Ory S, Jurdic P: A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts. J Cell Sci 2005;118:2901-2911.
39.
Takesono A, Heasman SJ, Wojciak-Stothard B, Garg R, Ridley AJ: Microtubules regulate migratory polarity through Rho/ROCK signaling in T cells. PLoS One 2010;5:e8774.
40.
Ikegami T, Nakamura M, Yamane J, Katoh H, Okada S, Iwanami A, Watanabe K, Ishii K, Kato F, Fujita H, Takahashi T, Okano HJ, Toyama Y, Okano H: Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury. Eur J Neurosci 2005;22:3036-3046.
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