Intimal hyperplasia (IH) results from excessive vascular smooth muscle cell (VSMC) proliferation, migration through the internal elastic lamina, and extracellular matrix (ECM) protein deposition, orchestrated by various physical and molecular factors in the vasculature. IH is a common complication following endovascular treatments or angioplasty procedures and remains poorly managed despite decades of research. Although many molecular factors contributing to IH have been identified over recent years, earlier studies have not fully integrated these discoveries. Recent research has largely concentrated on VSMC proliferation, migration, and dedifferentiation. This review aims to comprehensively elucidate the molecular pathways involved in all stages of IH development, including endothelial injury, the coagulation cascade, inflammation, ECM deposition, and vascular remodeling, to inform future therapeutic strategies. We extensively searched PubMed for relevant animal studies reporting molecular mechanism involved in formation of IH and included 56 articles. In total, we found 69 molecules and 6 pathways involved in all stages of IH. Among the molecular pathways involved, the Mitogen-activated Protein Kinase (MAPK), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Transforming Growth Factor Beta (TGF-β).pathways consistently emerge in almost each step of IH development. This highlights the need for a multifaceted and comprehensive treatment to prevent IH.
DégliseSBechelliCAllagnatF.Vascular smooth muscle cells in intimal hyperplasia, an update. Front Physiol. 2023;13:1081881.
2.
NguyenDTVokóBNyárádiBB, et al. Restenosis rates in patients with ipsilateral carotid endarterectomy and contralateral carotid artery stenting. PLoS One. 2022;17(2):e0262735.
3.
ColleranRMichelJRheudeT, et al. 27 angiographic restenosis after coronary stenting in patients with previous coronary bypass surgery. Br Cardiovasc Soc. 2017;103(S6):A16-A17.
4.
MwipatayiBPSharmaSDaneshmandA, et al. Durability of the balloon-expandable covered versus bare-metal stents in the Covered versus Balloon Expandable Stent Trial (COBEST) for the treatment of aortoiliac occlusive disease. J Vasc Surg. 2016;64(1):83-94.e1.
5.
MelnikTJordanOCorpatauxJMDelieFSaucyF.Pharmacological prevention of intimal hyperplasia: a state-of-the-art review. Pharmacol Ther. 2022;235:108157.
6.
NewbyACZaltsmanAB.Molecular mechanisms in intimal hyperplasia. J Pathol. 2000;190(3):300-309.
7.
ZhangDCaoYLiuDZhangJGuoY.The etiology and molecular mechanism underlying smooth muscle phenotype switching in intimal hyperplasia of vein graft and the regulatory role of microRNAs. Front Cardiovasc Med. 2022;9:935054.
8.
VijakumaranUYazidMDIdrusRBHRahmanMRASulaimanN.Molecular action of hydroxytyrosol in attenuation of intimal hyperplasia: a scoping review. Front Pharmacol. 2021;12:663266.
9.
PageMJMcKenzieJEBossuytPM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ Open. 2021;372:n71.
10.
WellsGSheaBO’ConnellD, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute; 2013. Accessed August 10, 2024. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
11.
ShoMShoESinghTM, et al. Subnormal shear stress-induced intimal thickening requires medial smooth muscle cell proliferation and migration. Exp Mol Pathol. 2002;72(2):150-160.
12.
KibbeMRLiJWatkinsSC, et al. Inducible nitric oxide synthase (iNOS) expression upregulates p21 and inhibits vascular smooth muscle cell proliferation through p42/44 mitogen-activated protein kinase activation and independent of p53 and cyclic guanosine monophosphate. J Vasc Surg. 2000;31(6):1214-1228.
13.
NaitoMHayashiTKuzuyaMFunakiCAsaiKKuzuyaF.Effects of fibrinogen and fibrin on the migration of vascular smooth muscle cells in vitro. Atherosclerosis. 1990;83(1):9-14.
14.
MaruyamaIShigetaKMiyaharaH, et al. Thrombin activates NF-κB through thrombin receptor and results in proliferation of vascular smooth muscle cells: role of thrombin in atherosclerosis and restenosis. Ann N Y Acad Sci. 1997;811(1):429-436.
15.
TanguayJFGeoffroyPSiroisM, et al. Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions with recombinant P-selectin glycoprotein ligand-1. Thromb Haemost. 2004;91(6):1186-1193.
16.
OzbenBDiz-KucukkayaRBilgeAKHancerVSOnculA.The association of P-selectin glycoprotein ligand-1 VNTR polymorphisms with coronary stent restenosis. J Thromb Thrombolysis. 2007;23(3):181-187.
17.
LiJKimKJeongSY, et al. Platelet protein disulfide isomerase promotes glycoprotein Ibα–mediated platelet-neutrophil interactions under thromboinflammatory conditions. Circulation. 2019;139(10):1300-1319.
18.
SmythSSReisEDZhangWFallonJTGordonRECollerBS.β3-integrin–deficient mice but not P-selectin–deficient mice develop intimal hyperplasia after vascular injury. Circulation. 2001;103(20):2501-2507.
19.
RemskarMLiHChyuKYShahPKCercekB.Absence of CD40 signaling is associated with an increase in intimal thickening after arterial injury. Circ Res. 2001;88(4):390-394.
20.
ShiXGuoLWSeedialSM, et al. TGF-β/Smad3 inhibit vascular smooth muscle cell apoptosis through an autocrine signaling mechanism involving VEGF-A. Cell Death Dis. 2014;5(7):e1317.
21.
ZhangXWangYHuW, et al. Interleukin-1/toll-like receptor-induced nuclear factor kappa B signaling participates in intima hyperplasia after carotid artery balloon injury in Goto-Kakizaki rats: a potential target therapy pathway. PLoS One. 2014;9(8):e103794.
22.
HanSXuSZhouJ, et al. Sam68 impedes the recovery of arterial injury by augmenting inflammatory response. J Mol Cell Cardiol. 2019;137:82-92.
23.
ShishidoTNozakiNTakahashiH, et al. Central role of endogenous toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury. Biochem Biophys Res Commun. 2006;345(4):1446-1453.
24.
CaiJZhongHWuJ, et al. Cathepsin L promotes vascular intimal hyperplasia after arterial injury. Mol Med. 2017;23(1):92-100.
25.
PatelVIDanielSLongoCR, et al. A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia. FASEB J. 2006;20(9):1418-1430.
26.
VanchinBOffringaEFriedrichJ, et al. MicroRNA-374b induces endothelial-to-mesenchymal transition and early lesion formation through the inhibition of MAPK7 signaling. J Pathol. 2019;247(4):456-470.
27.
WangWChenLShangC, et al. miR-145 inhibits the proliferation and migration of vascular smooth muscle cells by regulating autophagy. J Cell Mol Med. 2020;24(12):6658-6669.
28.
ZengZXiaLFanS, et al. Circular RNA circMAP3K5 acts as a microRNA-22-3p sponge to promote resolution of intimal hyperplasia via TET2-mediated smooth muscle cell differentiation. Circulation. 2021;143(4):354-371.
29.
LuanPJianWXuX, et al. NLRC5 inhibits neointima formation following vascular injury and directly interacts with PPARγ. Nat Commun. 2019;10(1):2882.
30.
ZhouYZhangMJLiBH, et al. PPARγ Inhibits VSMC proliferation and migration via attenuating oxidative stress through upregulating UCP2. PLoS One. 2016;11(5):e0154720.
31.
SchoberAZerneckeALiehnEA, et al. Crucial role of the CCL2/CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and CCL2 presentation on platelets. Circ Res. 2004;95(11):1125-1133.
32.
ZhanYKimSIzumiY, et al. Role of JNK, p38, and ERK in platelet-derived growth factor–induced vascular proliferation, migration, and gene expression. Arterioscler Thromb Vasc Biol. 2003;23(5):795-801.
33.
AsaharaTBautersCPastoreC, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation. 1995;91(11):2793-2801.
34.
FeinbergMWShimizuKLebedevaM, et al. Essential role for smad3 in regulating MCP-1 expression and vascular inflammation. Circ Res. 2004;94(5):601-608.
35.
TsaiSHollenbeckSTRyerEJ, et al. TGF-β through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am J Physiol Heart Circ Physiol. 2009;297(2):H540-H549.
36.
KomaravoluRKWaltmannMDKonaniahEJaeschkeAHuiDY.ApoER2 (apolipoprotein E receptor-2) deficiency accelerates smooth muscle cell senescence via cytokinesis impairment and promotes fibrotic neointima after vascular injury. Arterioscler Thromb Vasc Biol. 2019;39(10):2132-2144.
37.
SunHJZhaoMXRenXS, et al. Salusin-β promotes vascular smooth muscle cell migration and intimal hyperplasia after vascular injury via ROS/NFκB/MMP-9 pathway. Antioxid Redox Signal. 2016;24(18):1045-1057.
38.
JianDWangWZhouX, et al. Interferon-induced protein 35 inhibits endothelial cell proliferation, migration and re-endothelialization of injured arteries by inhibiting the nuclear factor-kappa B pathway. Acta Physiologica. 2018;223(3):e13037.
39.
ZhangYFuYZhangC, et al. MED1 Deficiency in macrophages accelerates intimal hyperplasia via ROS generation and inflammation. Oxid Med Cell Longev. 2021;2021:1-19.
40.
HolnessWSantoreTABrownGPFallonJTTaubmanMBIyengarR.Expression of Q227L-Gαs inhibits intimal vessel wall hyperplasia after balloon injury. Proc Natl Acad Sci U S A. 2001;98(3):1288-1293.
EdwardsJMAllooshMALongXL, et al. Adenosine A1 receptors in neointimal hyperplasia and in-stent stenosis in Ossabaw miniature swine. Coron Artery Dis. 2008;19(1):27-31.
43.
KouWXuXJiS, et al. The inhibition of the effect and mechanism of vascular intimal hyperplasia in Tiam1 knockout mice. Biochem Biophys Res Commun. 2018;497(1):248-255.
44.
ZuojunHLingyuHWeiH, et al. Interference of IP-10 expression inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in carotid artery: a new insight in the prevention of restenosis. Cell Biochem Biophys. 2012;62(1):125-135.
45.
JiangFZhangBZhangX, et al. miRNA 92a inhibits vascular smooth muscle cell phenotypic modulation and may help prevent in stent restenosis. Mol Med Rep. 2023;27(2):40.
46.
ZengZXiaLFanX, et al. Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair. J Clin Invest. 2019;129(3):1372-1386.
47.
GuMWangZFengFYangYSunXYangD.Inhibition of PIKfyve ameliorates the proliferation and migration of vascular smooth muscle cells and vascular intima hyperplasia by reducing mTORC1 activity. J Cardiovasc Pharmacol. 2022;79(5):739-748.
48.
WuHBWangZWShiF, et al. Avβ3 single-stranded DNA aptamer attenuates vascular smooth muscle cell proliferation and migration via Ras-PI3K/MAPK pathway. Cardiovasc Ther. 2020;2020:1-12.
49.
QianKFengLSunY, et al. Overexpression of salusin-α inhibits vascular intimal hyperplasia in an atherosclerotic rabbit model. Biomed Res Int. 2018;2018:1-9.
50.
LeeHYChungJWYounSW, et al. Forkhead transcription factor FOXO3a is a negative regulator of angiogenic immediate early gene CYR61, leading to inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ Res. 2007;100(3):372-380.
51.
ZhaoQZhouDYouH, et al. IFN-γ aggravates neointimal hyperplasia by inducing endoplasmic reticulum stress and apoptosis in macrophages by promoting ubiquitin-dependent liver X receptor-α degradation. FASEB J. 2017;31(12):5321-5331.
52.
WesselyRHengstLJaschkeB, et al. A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia. Hum Mol Genet. 2003;12(2):177-187.
53.
OwensL VXuLMarstonWA, et al. Overexpression of the focal adhesion kinase (p125FAK) in the vascular smooth muscle cells of intimal hyperplasia. J Vasc Surg. 2001;34(2):344-349.
54.
RongZLiFZhangR, et al. Inhibition of tiRNA-Gly-GCC ameliorates neointimal formation via CBX3-mediated VSMCs phenotypic switching. Front Cardiovasc Med. 2023;10:1030635.
55.
SrivastavaRRolyanHXieY, et al. TCF7L2 (transcription factor 7-like 2) regulation of GATA6 (GATA-binding protein 6)-dependent and -independent vascular smooth muscle cell plasticity and intimal hyperplasia. Arterioscler Thromb Vasc Biol. 2019;39(2):250-262.
56.
YamanouchiDKatoKRyerEJZhangFLiuB.Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis. Cardiovasc Res. 2010;85(3):434-443.
57.
BaiXMargaritiAHuY, et al. Protein kinase Cδ deficiency accelerates neointimal lesions of mouse injured artery involving delayed reendothelialization and vasohibin-1 accumulation. Arterioscler Thromb Vasc Biol. 2010;30(12):2467-2474.
58.
LevonenALInkalaMHeikuraT, et al. Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arterioscler Thromb Vasc Biol. 2007;27(4):741-747.
59.
LvLMengQYeMWangPXueG.STAT4 deficiency protects against neointima formation following arterial injury in mice. J Mol Cell Cardiol. 2014;74:284-294.
60.
ChenDKrasinskiKSylvesterAChenJNisenPDAndrésV.Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery. J Clin Invest. 1997;99(10):2334-2341.
61.
KenagyRD.Accumulation and loss of extracellular matrix during shear stress-mediated intimal growth and regression in baboon vascular grafts. J Histochem Cytochem. 2005;53(1):131-140.
62.
PorterKELoftusIMPetersonMBellPRFLondonNJMThompsonMM.Marimastat inhibits neointimal thickening in a model of human vein graft stenosis. Br J Surg. 2003;85(10):1373-1377.
63.
PorterKEThompsonMMLoftusIM, et al. Production and inhibition of the gelatinolytic matrix metalloproteinases in a human model of vein graft stenosis. Eur J Vasc Endovasc Surg. 1999;17(5):404-412.
64.
StrackeSKonnerKKöstlinI, et al. Increased expression of TGF-β1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas. Kidney Int. 2002;61(3):1011-1019.
65.
YanHPengXXuHZhuJDengC.Inhibition of aortic intimal hyperplasia and vascular smooth muscle proliferation and extracellular matrix protein expressions by Astragalus–Angelica combination. Evid Based Complement Alternat Med. 2018;2018(1):1508637.
66.
TranPKTran-LundmarkKSoininenRTryggvasonKThybergJHedinU.Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate–deficient perlecan. Circ Res. 2004;94(4):550-558.
67.
SunYZhangBXiaL.Effect of low wall shear stress on the morphology of endothelial cells and its evaluation indicators. Comput Methods Programs Biomed. 2021;208:106082.
68.
EbertMLASchmidtVFPfaffLvon ThadenAKimmMAWildgruberM. Animal models of neointimal hyperplasia and restenosis: species-specific differences and implications for translational research. JACC Basic Transl Sci. 2021;6(11):900-917.
69.
YaoGLiHZuoX, et al. Oscillatory shear stress promotes vein graft intimal hyperplasia via NADPH oxidase-related pathways. Front Surg. 2023;10:1073557.
70.
McQueenLWLadakSSZakkarM.Acute shear stress and vein graft disease. Int J Biochem Cell Biol. 2022;144:106173.
71.
ChengHZhongWWangL, et al. Effects of shear stress on vascular endothelial functions in atherosclerosis and potential therapeutic approaches. Biomed Pharmacother. 2023;158:114198.
72.
WentzelJJGijsenFJSchuurbiersJCvan der SteenAFSerruysPW.The influence of shear stress on in-stent restenosis and thrombosis. EuroIntervention. 2008;4(Suppl. C):C27-C32.
73.
PanS.Molecular mechanisms responsible for the atheroprotective effects of laminar shear stress. Antioxid Redox Signal. 2009;11(7):1669-1682.
74.
JeonHBooYC.Laminar shear stress enhances endothelial cell survival through a NADPH oxidase 2-dependent mechanism. Biochem Biophys Res Commun. 2013;430(2):460-465.
75.
LingCCookMDGrimmHAldokhayyilMGomezDBrownM.The effect of race and shear stress on CRP-induced responses in endothelial cells. Mediators Inflamm. 2021;2021:6687250.
76.
GagginiMGoriniFVassalleC.Lipids in atherosclerosis: pathophysiology and the role of calculated lipid indices in assessing cardiovascular risk in patients with hyperlipidemia. Int J Mol Sci. 2022;24(1):75.
77.
FolestadEKunathAWågsäterD.PDGF-C and PDGF-D signaling in vascular diseases and animal models. Mol Aspects Med. 2018;62:1-11.
78.
OlejarzWŁachetaDKubiak-TomaszewskaG.Matrix metalloproteinases as biomarkers of atherosclerotic plaque instability. Int J Mol Sci. 2020;21(11):3946.
79.
HallSAgrawalDK.Delivery of viral vectors for gene therapy in intimal hyperplasia and restenosis in atherosclerotic swine. Drug Deliv Transl Res. 2018;8(4):918-927.
80.
ZhaoJWuSZhangM, et al. Adventitial delivery of miR-145 to treat intimal hyperplasia post vascular injuries through injectable and in-situ self-assembling peptide hydrogels. Acta Biomater. 2024;173:247-260.
81.
KinlaySYoungMMSherrodRGagnonDR.Long-term outcomes and duration of dual antiplatelet therapy after coronary intervention with second-generation drug-eluting stents: the veterans affairs extended DAPT study. J Am Heart Assoc. 2023;12(2):e027055.
82.
LuKYeXChenY, et al. Research progress of drug eluting balloon in arterial circulatory system. Front Cardiovasc Med. 2024;11:1287852.
83.
KunduAMoliternoDJ.Drug-coated balloons for in-stent restenosis—finally leaving nothing behind for US patients. JAMA. 2024;331(12):1011.
84.
ShlofmitzEIantornoMWaksmanR.Restenosis of drug-eluting stents: a new classification system based on disease mechanism to guide treatment and state-of-the-art review. Circ Cardiovasc Interv. 2019;12(8):e007023.
85.
TorradoJBuckleyLDuránA, et al. Restenosis, stent thrombosis, and bleeding complications: navigating between Scylla and Charybdis. J Am Coll Cardiol. 2018;71(15):1676-1695.
