Background: Inflammation plays a key role in neointimal hyperplasia after an arterial injury. Chronic infectious disorders, such as periodontitis, are associated with an increased risk of cardiovascular diseases. However, the effects of a periodontal infection on vascular remodeling have not been examined. We assess the hypothesis that periodontal infection could promote neointimal formation after an arterial injury. Methods: Mice were implanted with subcutaneous chambers (n = 41). Two weeks after implantation, the femoral arteries were injured, and Porphyromonas gingivalis (n = 21) or phosphate-buffered saline (n = 20) was injected into the chamber. The murine femoral arteries were obtained for the histopathological analysis. The expression level of mRNA in the femoral arteries was analyzed using quantitative reverse transcriptase polymerase chain reaction (n = 19–20). Results: The intima/media thickness ratio in the P. gingivalis infected group was found to be significantly increased in comparison to the non-infected group. The expression of matrix metalloproteinase-2 mRNA was significantly increased in the P. gingivalis infected group compared to the non-infected group. Conclusion: These findings demonstrate that P. gingivalis injection can promote neointimal formation after an arterial injury. Periodontitis may be a critical factor in the development of restenosis after arterial intervention.

Gibson FC 3rd, Hong C, Chou HH, Yumoto H, Chen J, Lien E, Wong J, Genco CA: Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004;109:2801–2806.
Spahr A, Klein E, Khuseyinova N, Boeckh C, Muche R, Kunze M, Rothenbacher D, Pezeshki G, Hoffmeister A, Koenig W: Periodontal infections and coronary heart disease: role of periodontal bacteria and importance of total pathogen burden in the Coronary Event and Periodontal Disease (CORODONT) study. Arch Intern Med 2006;166:554–559.
Janket SJ, Baird AE, Chuang SK, Jones JA: Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:559–569.
Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ: Identification of periodontal pathogens in atheromatous plaques. J Periodontol 2000;71:1554–1560.
Fiehn NE, Larsen T, Christiansen N, Holmstrup P, Schroeder TV: Identification of periodontal pathogens in atherosclerotic vessels. J Periodontol 2005;76:731–736.
D’Aiuto F, Parkar M, Nibali L, Suvan J, Lessem J, Tonetti MS: Periodontal infections cause changes in traditional and novel cardiovascular risk factors: results from a randomized controlled clinical trial. Am Heart J 2006;151:977–984.
Rajasuo A, Perkki K, Nyfors S, Jousimies-Somer H, Meurman JH: Bacteremia following surgical dental extraction with an emphasis on anaerobic strains. J Dent Res 2004;83:170–174.
Heimdahl A, Hall G, Hedberg M, Sandberg H, Soder PO, Tuner K, Nord CE: Detection and quantitation by lysis-filtration of bacteremia after different oral surgical procedures. J Clin Microbiol 1990;28:2205–2209.
Conner HD, Haberman S, Collings CK, Winford TE: Bacteremias following periodontal scaling in patients with healthy appearing gingiva. J Periodontol 1967;38:466–472.
Debelian GJ, Olsen I, Tronstad L: Bacteremia in conjunction with endodontic therapy. Endod Dent Traumatol 1995;11:142–149.
Savarrio L, Mackenzie D, Riggio M, Saunders WP, Bagg J: Detection of bacteremias during non-surgical root canal treatment. J Dent 2005;33:293–303.
Tonetti MS: Periodontitis and risk for atherosclerosis: an update on intervention trials. J Clin Periodontol 2009;36(suppl 10):15–19.
Jain A, Batista EL Jr, Serhan C, Stahl GL, Van Dyke TE: Role for periodontitis in the progression of lipid deposition in an animal model. Infect Immun 2003;71:6012–6018.
Yamamoto Y, Watari Y, Brydun A, Yoshizumi M, Akishita M, Horiuchi M, Chayama K, Oshima T, Ozono R: Role of the angiotensin II type 2 receptor in arterial remodeling after wire injury in mice. Hypertens Res 2008;31:1241–1249.
Greenlee KJ, Corry DB, Engler DA, Matsunami RK, Tessier P, Cook RG, Werb Z, Kheradmand F: Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation. J Immunol 2006;177:7312–7321.
Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT: Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000;106:55–62.
Mukherjee R, Brinsa TA, Dowdy KB, Scott AA, Baskin JM, Deschamps AM, Lowry AS, Escobar GP, Lucas DG, Yarbrough WM, Zile MR, Spinale FG: Myocardial infarct expansion and matrix metalloproteinase inhibition. Circulation 2003;107:618–625.
Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994;94:2493–2503.
Ogawa M, Suzuki J, Hishikari K, Takayama K, Tanaka H, Isobe M: Clarithromycin attenuates acute and chronic rejection via matrix metalloproteinase suppression in murine cardiac transplantation. J Am Coll Cardiol 2008;51:1977–1985.
Lijnen HR, Soloway P, Collen D: Tissue inhibitor of matrix metalloproteinases-1 impairs arterial neointima formation after vascular injury in mice. Circ Res 1999;85:1186–1191.
Tavakoli S, Razavian M, Zhang J, Nie L, Marfatia R, Dobrucki LW, Sinusas AJ, Robinson S, Edwards DS, Sadeghi MM: Matrix metalloproteinase activation predicts amelioration of remodeling after dietary modification in injured arteries. Arterioscler Thromb Vasc Biol 2011;31:102–109.
Aoyama N, Suzuki J, Wang D, Ogawa M, Kobayashi N, Hanatani T, Takeuchi Y, Izumi Y, Isobe M: Porphyromonas gingivalis promotes murine abdominal aortic aneurysms via matrix metalloproteinase-2 induction. J Periodontal Res 2011;46:176–183.
Suzuki J, Ogawa M, Muto S, Yamaguchi Y, Itai A, Isobe M: The effects of pharmacological PAI-1 inhibition on thrombus formation and neointima formation after arterial injury. Expert Opin Ther Targets 2008;12:783–794.
Inagaki H, Suzuki J, Ogawa M, Taniyama Y, Morishita R, Isobe M: Ultrasound-microbubble-mediated NF-kappaB decoy transfection attenuates neointimal formation after arterial injury in mice. J Vasc Res 2006;43:12–18.
Sata M, Maejima Y, Adachi F, Fukino K, Saiura A, Sugiura S, Aoyagi T, Imai Y, Kurihara H, Kimura K, Omata M, Makuuchi M, Hirata Y, Nagai R: A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. J Mol Cell Cardiol 2000;32:2097–2104.
Ogawa M, Suzuki J, Kosuge H, Takayama K, Nagai R, Isobe M: The mechanism of anti-inflammatory effects of prostaglandin E2 receptor 4 activation in murine cardiac transplantation. Transplantation 2009;87:1645–1653.
Lyons SR, Griffen AL, Leys EJ: Quantitative real-time PCR for Porphyromonas gingivalis and total bacteria. J Clin Microbiol 2000;38:2362–2365.
Li L, Messas E, Batista EL Jr, Levine RA, Amar S: Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 2002;105:861–867.
Meurman JH, Sanz M, Janket SJ: Oral health, atherosclerosis, and cardiovascular disease. Crit Rev Oral Biol Med 2004;15:403–413.
Houri-Haddad Y, Soskoine WA, Shapira L: Immunization to Porphyromonas gingivalis enhances the local pro-inflammatory response to subcutaneous bacterial challenge. J Clin Periodontol 2001;28:476–482.
Lin D, Smith MA, Champagne C, Elter J, Beck J, Offenbacher S: Porphyromonas gingivalis infection during pregnancy increases maternal tumor necrosis factor alpha, suppresses maternal interleukin-10, and enhances fetal growth restriction and resorption in mice. Infect Immun 2003;71:5156–5162.
Lin YY, Huang JH, Lai YY, Huang HC, Hu SW: Tissue destruction induced by Porphyromonas gingivalis infection in a mouse chamber model is associated with host tumor necrosis factor generation. Infect Immun 2005;73:7946–7952.
Holt SC, Kesavalu L, Walker S, Genco CA: Virulence factors of Porphyromonas gingivalis. Periodontol 2000 1999;20:168–238.
Grenier D, La VD: Proteases of Porphyromonas gingivalis as important virulence factors in periodontal disease and potential targets for plant-derived compounds: a review article. Curr Drug Targets 2011;12:322–331.
Belanger M, Kozarov E, Song H, Whitlock J, Progulske-Fox A: Both the unique and repeat regions of the Porphyromonas gingivalis hemagglutin A are involved in adhesion and invasion of host cells. Anaerobe 2011;18:128–134.
Zhang MZ, Li CL, Jiang YT, Jiang W, Sun Y, Shu R, Liang JP: Porphyromonas gingivalis infection accelerates intimal thickening in iliac arteries in a balloon-injured rabbit model. J Periodontol 2008;79:1192–1199.
Hanazawa S, Kawata Y, Takeshita A, Kumada H, Okithu M, Tanaka S, Yamamoto Y, Masuda T, Umemoto T, Kitano S: Expression of monocyte chemoattractant protein 1 (MCP-1) in adult periodontal disease: increased monocyte chemotactic activity in crevicular fluids and induction of MCP-1 expression in gingival tissues. Infect Immun 1993;61:5219–5224.
Stark VK, Hoch JR, Warner TF, Hullett DA: Monocyte chemotactic protein-1 expression is associated with the development of vein graft intimal hyperplasia. Arterioscler Thromb Vasc Biol 1997;17:1614–1621.
Furukawa Y, Matsumori A, Ohashi N, Shioi T, Ono K, Harada A, Matsushima K, Sasayama S: Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries. Circ Res 1999;84:306–314.
Kang IC, Kuramitsu HK: Induction of monocyte chemoattractant protein-1 by Porphyromonas gingivalis in human endothelial cells. FEMS Immunol Med Microbiol 2002;34:311–317.
Bodet C, Chandad F, Grenier D: Porphyromonas gingivalis-induced inflammatory mediator profile in an ex vivo human whole blood model. Clin Exp Immunol 2006;143:50–57.
Kenagy RD, Hart CE, Stetler-Stevenson WG, Clowes AW: Primate smooth muscle cell migration from aortic explants is mediated by endogenous platelet-derived growth factor and basic fibroblast growth factor acting through matrix metalloproteinases 2 and 9. Circulation 1997;96:3555–3560.
Johnson JL, Dwivedi A, Somerville M, George SJ, Newby AC: Matrix metalloproteinase (MMP)-3 activates MMP-9 mediated vascular smooth muscle cell migration and neointima formation in mice. Arterioscler Thromb Vasc Biol 2011;31:e35–e44.
Zou Y, Qi Y, Roztocil E, Davies MG: Patterns of gelatinase activation induced by injury in the murine femoral artery. J Surg Res 2009;154:135–142.
Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, Ivan E: Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res 2002;91:852–859.
Ramseier CA, Kinney JS, Herr AE, Braun T, Sugai JV, Shelburne CA, Rayburn LA, Tran HM, Singh AK, Giannobile WV: Identification of pathogen and host-response markers correlated with periodontal disease. J Periodontol 2009;80:436–446.
Soder PO, Meurman JH, Jogestrand T, Nowak J, Soder B: Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in blood as markers for early atherosclerosis in subjects with chronic periodontitis. J Periodontal Res 2009;44:452–458.
Alpagot T, Bell C, Lundergan W, Chambers DW, Rudin R: Longitudinal evaluation of GCF MMP-3 and TIMP-1 levels as prognostic factors for progression of periodontitis. J Clin Periodontol 2001;28:353–359.
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