Perivascular mast cells promote neointimal elastin deposition and suppress chronic vein graft restenosis in hyperlipidaemic mice

Abstract

Aim: Mast cells are versatile innate immune cells and are reported to promote vascular inflammation and neointimal lesion formation, thereby contributing to the development of vascular stenosis and atherosclerosis. However, it is not clear whether mast cells also regulate vascular matrix remodelling in established neointima. This study addressed the hypothesis that perivascular mast cells regulate neointimal matrix remodelling using a mouse vein graft model.

Methods: The impact of mast cells on neointimal remodelling was investigated using mast cell-deficient animals in both normolipidaemic (Kit^W-sh/W-sh) and hyperlipidaemic (apoE^-/-Kit^W-sh/W-sh) conditions. The effect of perivascular mast cells on vascular matrix remodelling, including collagen and elastin deposition, was investigated using a local mast cell reconstitution method that selectively repopulated mast cells around the carotid artery (where the vein graft was inserted) in Kit^W-sh/W-sh mice.

Results: In normolipidaemic vein grafts (Kit^W-sh/W-sh vs. the wild type control C57BL/6J), collagen synthesis was not affected by mast cell deficiency at 4 weeks. In contrast, neointimal elastin was reduced by 6.5-fold in mast cell-deficient Kit^W-sh/W-sh mice, which was prevented by perivascular mast cell reconstitution. Mast cell deficiency induced a similar reduction in neointimal elastin in hyperlipidaemic mice (apoE^-/-Kit^W-sh/W-sh vs. apoE^-/-), with a significant increase in cell proliferation and neointimal area at 4 weeks.

Conclusion: Mast cells appear to promote elastin deposition in vein grafts and this may lead to further suppression of cell proliferation and neointimal thickening under hyperlipidaemic conditions.

Keywords

Mast cells / elastin / chronic restenosis / neointima / vein graft

References

[1] St John AL.Innate immunity and its regulation by mast cells..J Immunol2013;190:4458-63 PMCID:PMC3645001

[2] Kennedy S,Wadsworth RM,Maffia P.Mast cells and vascular diseases..Pharmacol Ther2013;138:53-65

[3] Sun J,Wolters PJ,Kitamoto S,MacFarlane LA,Shi GP.Mast cells promote atherosclerosis by releasing proinflammatory cytokines..Nat Med2007;13:719-24

[4] Zhang J,Lindholt JS,Sinnamon M,Adachi R,Thompson RW.Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation..Circ Res2011;108:1316-27 PMCID:PMC3108141

[5] de Vries MR,Schepers A,Woodruff TM,Hamming JF,Bot I.Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease..Cardiovasc Res2013;97:311-20

[6] Bot I,Kovanen PT.Mast cells as effectors in atherosclerosis..Arterioscler Thromb Vasc Biol2015;35:265-71 PMCID:PMC4304944

[7] Bot I,Zernecke A,van Berkel TJ,Biessen EA.Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice..Circulation2007;115:2516-25

[8] Wang J,Tia V,Chen H,Sukhova GK.Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice..Atherosclerosis2013;229:304-9 PMCID:PMC3724238

[9] Tang Y,Wang S,Tang C,Sun YH.Mast cell degranulator compound 48-80 promotes atherosclerotic plaque in apolipoprotein E knockout mice with perivascular common carotid collar placement..Chin Med J (Engl)2009;122:319-25

[10] Grimbaldeston MA,Piliponsky AM,Tam SY.Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo..Am J Pathol2005;167:835-48

[11] Wu J.Neointimal hyperplasia, vein graft remodeling, and long-term patency..Am J Physiol Heart Circ Physiol2009;297:H1194-5 PMCID:PMC2770752

[12] Owens CD,Rahman AS.Vein graft failure..J Vasc Surg2015;61:203-16 PMCID:PMC4391818

[13] Wu J,Kennedy S.Inhibition of inducible nitric oxide synthase promotes vein graft neoadventitial inflammation and remodelling..J Vasc Res2011;48:141-9

[14] Wu J,Cambrook H,MacRitchie N,Wadsworth RM,Kennedy S.Perivascular mast cells regulate vein graft neointimal formation and remodeling..Peer J2015;3:e1192 PMCID:PMC4548472

[15] de Vries MR,Jukema JW,Quax PH.Vein graft failure: from pathophysiology to clinical outcomes..Nat Rev Cardiol2016;13:451-70

[16] de Vries MR,Schepers A,Woodruff TM,Hamming JF,Bot I.Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease..Cardiovasc Res2013;97:311-20

[17] Kothapalli D,Rader DJ,Lund-Katz S.Apolipoprotein E-mediated cell cycle arrest linked to p27 and the Cox2-dependent repression of miR221/222..Atherosclerosis2013;227:65-71 PMCID:PMC3638207

[18] Lannoy M,Jacob MP.The function of elastic fibers in the arteries: beyond elasticity..Pathol Biol2014;62:79-83

[19] Carlsson P.Heparin biosynthesis..In: Lever R, Mulloy B, Page CP, editors. Handbook of experimental pharmacology.2012;Berlin, HeidelbergSpringer Berlin Heidelberg23-41

[20] Teomim D,Golomb G,Mayberg M.Perivascular delivery of heparin for the reduction of smooth muscle cell proliferation after endothelial injury..J Control Release1999;60:129-42

[21] Saitow C,Castellot JJ.Heparin stimulates elastogenesis: application to silk-based vascular grafts..Matrix Biol2011;30:346-55 PMCID:PMC4091834

[22] Tu Y.Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides..Matrix Biol2010;29:152-9

[23] Cain SA,Gallagher J,Bax DV,Shuttleworth CA.Fibrillin-1 interactions with heparin: implications for microfibril and elastic fiber assembly..J Biol Chem2005;280:30526-37

[24] Tu Y.Glycosaminoglycan-mediated coacervation of tropoelastin abolishes the critical concentration, accelerates coacervate formation, and facilitates spherule fusion: implications for tropoelastin microassembly..Biomacromolecules2008;9:1739-44

[25] Edelman ER,Karnovsky MJ.Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury..Proc Natl Acad Sci U S A1990;87:3773-7 PMCID:PMC53985

[26] Capron L,Heudes D,Bruneval P.Repeated balloon injury of rat aorta: a model of neointima with attenuated inhibition by heparin..Arterioscler Thromb Vasc Biol1997;17:1649-56

[27] Chajara A,Peronneau I,Basset A.Effects of heparinoids on the sclerotic reaction of rat thoracic aorta to injury: comparison between standard and low-molecular-weight heparins in vitro and in vivo..J Cardiovasc Pharmacol1994;23:995-1003

[28] Guyton JR,Clowes AW.Inhibition of rat arterial smooth muscle cell proliferation by heparin. In vivo studies with anticoagulant and nonanticoagulant heparin..Circ Res1980;46:625-34

[29] Ellis SG,Wilentz J,King SB.Effect of 18- to 24-hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty..Am Heart J1989;117:777-82

[30] Kunder CA,Li G,Berwin B,Abraham SN.Mast cell-derived particles deliver peripheral signals to remote lymph nodes..J Exp Med2009;206:2455-67 PMCID:PMC2768851

[31] Marx SO,Marks AR.Vascular smooth muscle cell proliferation in restenosis..Circ Cardiovasc Interv2011;4:104-11 PMCID:PMC3816546

[32] Matter CM,von Lukowicz T,Lohmann C,Kilic U,Ha SW,Hermann DM.Increased balloon-induced inflammation, proliferation, and neointima formation in apolipoprotein E (ApoE) knockout mice..Stroke2006;37:2625-32

[33] Liu CL,Shi GP.Interaction between allergic asthma and atherosclerosis..Transl Res2016;174:5-22 PMCID:PMC4826642

[34] Wulff BC,Meleski MA,Schrementi ME.Mast cells contribute to scar formation during fetal wound healing..J Invest Dermatol2012;132:458-65 PMCID:PMC3258379

[35] Wilgus TA.The importance of mast cells in dermal scarring..Adv Wound Care (New Rochelle)2014;3:356-65 PMCID:PMC3985512

[36] Pellicoro A,Ramachandran P,Fallowfield JA,Hartland SN,Duffield JS,Forbes SJ.Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis..Hepatology2012;55:1965-75

[37] Gonzalez S,Kochevar IE.Chronic photodamage in skin of mast cell-deficient mice..Photochem Photobiol1999;70:248-53

[38] Grimbaldeston MA,Finlay-Jones JJ.The effect of ultraviolet radiation exposure on the prevalence of mast cells in human skin..Br J Dermatol2003;148:300-6

[39] Farrell DJ,Walls AF,Bennett MK.Intrahepatic mast cells in chronic liver diseases..Hepatology1995;22:1175-81

[40] Jeong WI,Park SJ,Jeong KS.Kinetics of macrophages, myofibroblasts and mast cells in carbon tetrachloride-induced rat liver cirrhosis..Anticancer Res2002;22:869-77