MEDICINE

Inflammatory Growth Factors and In-Stent Restenosis: Effectof Cytokines and Growth Factors

Mohsen Maleknia1,2,3 & Narges Ansari4 & Habib Haybar5 & Mahmood Maniati1 & Najmaldin Saki1,3

Accepted: 12 February 2020# Springer Nature Switzerland AG 2020

AbstractFollowing stent implantation and vascular injury, restenosis is one of the prominent clinical problems due to thesynergism effects of inflammatory cytokines and growth factors. Restenosis development is accompanied by increasedproliferation and migration of vascular smooth muscle cells (VSMCs) into the intimal region. The content has beenobtained from PubMed database and the Google Scholar search engine through searching English-language articles(1989–2019) using keywords “Vascular injury,” “Restenosis,” “Growth factors,” “Cytokines,” and “Smooth musclecells.” After the vascular injury, the secretion of inflammatory factors can stimulate inflammatory cells, which lead tothe release of growth factors. This can stimulate the migration of VSMCs and neointimal hyperplasia, and, as a result,lead to restenosis. Inflammatory cytokines, such as transforming growth factor-beta (TGFβ), often stimulate growthfactors such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), which can accelerate therestenosis process. Other cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in the initialinflammation inhibit restenosis by affecting insulin-like growth factor binding proteins (IGFBPs). Considering thesynergism effects of inflammatory cytokines and growth factors in the pathogenesis of restenosis, it is expected thatthese factors can be used as prognostic markers with therapeutic purposes.

Keywords Vascular injury . Restenosis . Growth factor . Cytokines . Smoothmuscle cells

Introduction

In-stent restenosis (ISR) is defined as in-stent narrowingwhich more occurs in 2 months after stent implantation in

coronary arteries, as a result of vascular injury and the releaseof stent material into the bloodstream [1]. ISR increases theprobable occurrence of angina, acute myocardial infarction(AMI), malignant arrhythmia, stroke, etc. which lead to death

Highlights•PDGF is considered as prime culprit among growth factors in thepathogenesis of restenosis.•Inflammatory cytokines can stimulate VSMC migration by recruitingmonocytes and releasing growth factors.•VEGF can be used to inhibit restenosis because of its revascularizationand re-endothelialization properties.

This article is part of the Topical Collection on Medicine

* Najmaldin Sakinajmaldinsaki@gmail.com

1 Thalassemia & Hemoglobinopathy Research Center, HealthResearch Institute, Ahvaz Jundishapur University of MedicalSciences, Ahvaz, Iran

2 Student Research Committee, Ahvaz Jundishapur University ofMedical Sciences, Ahvaz, Iran

3 Department of Clinical Laboratory Sciences, School of AlliedMedical Sciences, Ahvaz Jundishapur University of MedicalSciences, Ahvaz, Iran

4 Isfahan Bone Metabolic Disorders Research Center, Department ofInternal Medicine, School of Medicine, Isfahan University ofMedical Sciences, Isfahan, Iran

5 Atherosclerosis Research Center, Ahvaz Jundishapur University ofMedical Sciences, Ahvaz, Iran

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without timely rescue [2]. After vascular injury, inflammatoryactivation and the secretion of growth factors (by inflamma-tory cells) lead to monocyte recruitment, stimulation of inti-mal formation, and increased proliferation and migration ofvascular smooth muscle cells (VSMCs) to the intimal region.Increasing intimal hyperplasia and restenosis is the sequel tothese conditions [3]. During inflammation, inflammatory cy-tokines affect fibroblasts, platelets, and endothelial cells andcause changes in secretion of growth factors such as platelet-derived growth factor (PDGF), insulin-like growth factor(IGF), fibroblast growth factor (FGF), and vascular endothe-lial growth factor (VEGF). Also, inflammatory cytokines canalter the organization of epithelial cells, recruit inflammatorycells into the inflammation site, and change the structure of theextracellular matrix (ECM) [4]. Sometimes the effects of in-flammatory cytokines, such as transforming growth factor-beta (TGFβ) and interleukin-18 (IL-18), boost the functionof growth factors such as PDGF and VEGF, and also increasethe synthesis of proteoglycans, collagen, and VSMC prolifer-ation, which increases the occurrence of restenosis [5, 6]. As aresult, measuring serum levels of these cytokines and growthfactors can be very useful as prognostic and diagnosticmarkers to predict the occurrence of restenosis after stent im-plantation [7].

On the contrary, other cytokines such as tumor necrosisfactor-alpha (TNF-α), IL-1α, and IL-1β along with IFNγ inthe inflammation site inhibit the process of restenosis by in-ducing IGF binding protein (IGFBPs) and inhibiting the syn-thesis of ECM components and collagen [8]. Also, due to therevascularization and re-endothelialization properties ofVEGF, it can reduce VSMC proliferation that inhibits reste-nosis. On the other hand, in the presence of inflammatorycytokines such as TGFβ and increased expression of the basicfibroblast growth factor (bFGF), VEGF can increase the oc-currence of restenosis. Therefore, VEGF can be considered asa dual-function growth factor associated with restenosis [9,10].

Given the synergism effects of inflammation and growthfactors in restenosis, antagonists, protein kinase inhibitors,and gene therapy can be used to control the effects of growthfactors. In addition, anti-inflammatory proteins, recombinantantibodies, and anti-selectin antibodies can be used to inhibitthe effects of inflammatory cytokines and monocyte recruit-ment [11–14]. Of course, the presence of the polymorphism inanti-inflammatory proteins, which reduces VSMC prolifera-tion, can play a role in resistance to restenosis in patientsrequiring stent implantation [15]. Therefore, it could be ar-gued that the proliferation of VSMCs and their migration tothe intima region have a key role in the induction of restenosis,which can be affected by inflammatory cytokines and functionof growth factors. It could also be suggested that evaluation ofserum levels of inflammatory cytokines and growth factorscan be regarded as useful prognostic and diagnostic markers

for improving clinical management and choosing effectivetherapeutic strategies.

Growth Factors Affected by InflammatoryFactors in Restenosis

The relationship between inflammation and restenosis, as wellas the effect of inflammatory cytokines on growth factors, canprovide useful information about prognosis and clinical man-agement of this problem. After stent implantation and vascularinjury, the chances of developing inflammation can increasedue to overexpression of selectins, adhesion molecules, therecruiting of monocytes, and other inflammatory cells to theinjured area [16]. The first step is the rolling phenomenoncarried out through selectins binding to carbohydrate ligandsat the leukocyte surface, which contribute to intimal hyperpla-sia [17]. For example, increasing the serum level of E-selectinis closely associated with an increased risk of restenosis andcan be regarded as a prognostic marker in these patients [15].Similarly, increasing the serum level of P-selectin along withinflammatory cytokines leads to platelet activation and stim-ulating growth factors such as PDGF which increase thechance of restenosis [18]. It is noteworthy that the mechanismof endothelial cell activation upon ISR plays an important rolein vascular injury. Early ISR is associated with subsequentendothelium dysfunction with uncontrolled neointimal prolif-eration [19]. Percutaneous coronary intervention (PCI) causesEC activation accompanied by enhanced E-selectin and vas-cular cell adhesion molecule-1 (VCAM-1) expressionresulting in their elevated plasma concentrations [20]. Bothadhesion receptors are expressed on activated ECs stimulatedby TNF-α or other inflammatory cytokines via increased tran-scriptional regulation, which are then involved in leukocytemigration to ECs. Also, soluble E-selectin and VCAM-1 con-centrations as sensitive laboratory parameters can indicate ahigher level of EC activation in bare-metal stented patientswith ISR compared with drug-eluting stented subjects withoutany complication [21].

Studies have been showed that the use of recombinant an-tibodies against P-selectin ligand-1 could reduce the severityof restenosis by reducing neointimal hyperplasia so that theseantibodies can be used in the pre-treatment of patients requir-ing stent implantation [22]. In the next step, recruitment ofinflammatory cells (such as fibroblasts, monocytes, and plate-lets which produce growth factors) to the site of inflammationincreases the expression of the adhesion molecules includingCAMS, which increase the probability of restenosis [23]. Theβ-integrin molecule, Mac-1 (CD11b/CD18), also plays an im-portant role in restenosis through recruitment of monocytes[24]. In the meantime, the secretion of inflammatory cytokinescan affect the growth factors involved in inflammation andcontribute to the stimulation or inhibition of restenosis

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(Fig. 1). For example, TGFβ by enhancing collagen synthesisand matrix accumulation can help PDGF in increasing theproliferation of VSMCs and their migration to the intimalregion [25, 26]. Some inflammatory cytokines such asTNF-α, IL-1α, and IL-1β, unlike TGFβ, inhibit IGFBP-induced proteoglycan synthesis, thus contributing to the re-duction of in-stent restenosis [8, 27]. In studies conductedon rat models, the IL-18 signaling received by the α/β IL-18R (located on the SMC surface) can contribute to neointi-mal formation and restenosis by enhancing VSMC prolifera-tion and migration [5]. According to studies, the significanceof IL-1α signaling as a risk factor for VSMC proliferation andneointimal hyperplasia has been established. For this reason,the use of IL-1α blockers such as Xilonix (a monoclonalantibody that specifically targets IL-1α) can be an effectivetherapeutic to prevent restenosis [28]. Of course, the co-operation of several inflammatory cytokines may have differ-ent effects on the performance of growth factors. For example,in addition to stimulating growth factors such as PDGF andVEGF, TNF-α secretion along with IL-1 and TGFβ in theinflammatory lesion causes upregulation in the synthesis offibrillar proteins (such as collagens), proteoglycans, and gly-coproteins (such as laminin and chondronectin). In the acutephase of inflammation, increased level of C-reactive protein(CRP), serum amyloid A (SSA), and fibronectin results inboth increasing the recruitment of growth factor–producingcells and intensity of vascular injury caused by stent implan-tation [15, 29, 30]. For instance, higher levels of high-sensitive C-reactive protein (hs-CRP) in coronary heart dis-ease (CHD) patients after stent implantation increase risk ofISR and associated with poor prognosis. Therefore, measuringhs-CRP as a prognostic marker for restenosis is an effectivemethod in both admission and follow-up [2].

Due to the role of inflammatory cytokines and growth fac-tors in the pathogenesis of ISR, there are several methods forinhibiting it. Genetically, altering the expression of the genesencoding inflammatory proteins or anti-inflammatory proteinscan change cytokine expression pattern and thereby stimulate/inhibit restenosis [15]. For example, polymorphism in theheme oxygenase 1 (HO-1) encoding gene, which is an anti-inflammatory protein, can be useful in controlling ISR byinhibiting proliferation of VSMCs and reducing the effectsof PDGF [31]. Also, in patients who use oral immunosuppres-sive treatments such as prednisone after stent implantation,angiogenesis and inflammatory cytokines are reduced, so theoral immunosuppressive treatment can be used as a safe andeffective way to control restenosis [32, 33]. Besides, statins(such as pitavastatin which contain anti-inflammatory proper-ties), through reducing the function of growth factors such asPDGF and down-regulating neointimal hyperplasia, can sup-press restenosis after stenting [34, 35]. Recently, gene therapy,such as therapeutic genes that encode VEGF, MCP-1, eNOS,and pENTPDase, has been used as a promising strategy to

prevent restenosis [24]. Therefore, due to the central role ofcell proliferation induced by growth factors alongside inflam-matory cytokines, identifying the function of factors and cellscan be a prognostic marker in clinical management and en-hancement of the patient’s condition.

PDGF as a Prime Culprit in the Growthof VSMCs

PDGF is secreted from macrophages (MQs), monocytes, andother cells that play a role in inflammation, but the main cellssecreting it are platelets. PDGF acts as a robust chemotacticagent to recruit MQs and monocytes, and a powerful stimula-tor for the migration and proliferation of VSMCs [36].Evidence suggests that PDGF is also useful in the migrationof fibroblasts that can increase endothelial cell proliferation[37].

The PDGF receptor (PDGFR) has alpha and beta chainsthat appear in the form of homodimers (PDGFR α/α) or het-erodimers (PDGFR β/β) at the cell surface [12]. PDGF bindsto the β chain in PDGFR (with high affinity) and stimulatessignaling in the growth pathway and Ras pathway, whichincreases cell proliferation. It seems that among the growthfactors, PDGF is the main culprit involved in restenosis ex-tending [38]. PDGF increases the migration and proliferationof VSMC from the media to the lumen [39]. After vascularinjury, inflammation-induced TGFβ through increasing colla-gen synthesis, matrix accumulation, and induction of differ-entiation in myofibroblasts can help PDGF in stimulating theproliferation of VSMC and neointimal formation [40]. It hasalso been observed that secretion of TGFβ by recruitingmonocytes to the site of inflammation can boost the activityof PDGF [25]. Therefore, it is believed that increased inflam-mation of TGFβ secretion can increase the likelihood of ISR.Alternatively, the PDGF may directly affect endothelial cellfunctions. Although various studies have shown that thePDGFR is not expressed on the endothelial cells, other studieshave suggested that endothelial cells can express the PDGFRunder inflammatory conditions [41]. Given that the endothe-lial cells are also capable of producing the PDGF, it may besaid that autocrine or paracrine activation of endothelial cells(under the influence of their PDGF secretion) can lead toincreased endothelial cell proliferation and stimulation of an-giogenesis in inflammatory conditions [41, 42].

Although several studies have been conducted to reducethe effect of PDGF, most of these studies are focused on therole of growth signaling pathway and cell cycle inhibition[38]. AG1295 is an old and potent PDGF blocker. It can eitherinhibit the migration and proliferation of SMCs. Also, imatin-ib mesylate (a PDGF receptor tyrosine kinase inhibitor) byinhibiting the phosphorylation of PDGF receptor β could in-hibit SMC proliferation [24]. Anti-PDGF Ig can inhibit the

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PDGF-stimulating effect and prevent its chemotactic effect,thus is useful in the treatment of ISR [43]. Under circum-stances where patients with implantation stents also suffer

from neoplasmic malignancies, it is possible to use type IIprotein kinase inhibitors such as axitinib and nintedanib,which inhibit PDGFR β and α/β PDGFR, respectively [12].

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Other useful methods for reducing restenosis include the useof TAK-733, which has anti-proliferative and anti-migratoryproperties for VSMC, but it does not affect endothelial cells.After balloon injury, TAK-733 can inhibit angiotensin II stim-ulation and neointimal hyperplasia and cause downregulationin the inflammatory signals. Additionally, it has anti-inflammatory properties, which decrease the expression ofintercellular adhesion molecule 1 (ICAM-1) and VCAM-1(which is involved in activating VSMCs), and impairs mono-cyte adhesion [44, 45]. Therefore, it can be argued that the useof type II protein kinase inhibitors and TAK-733, which in-hibit anti-proliferative and anti-inflammatory properties, isrecommended to improve the patient’s condition.

Induction of Restenosis by IGF

Most cells in the body can synthesize IGF, but type 1 and type2 are generally synthesized in the liver [46]. IGF is a type ofendocrine mediator that has a half-life of about a few minutes,but if it binds to one of its seven receptors at the cell surface(IGFBPs), its half-life lasts for 15 h [47]. IGFBP-3 has moreaffinity for binding to IGF I and IGF II. However, most of theIGF functions are regulated by the IGF-1receptor, which isassociated with an intracellular tyrosine kinase. IGFBP-4 isalso the most significant receptor produced by VSMCs, whichcan regulate IGF-1 activity. The mechanism of action ofIGFBPs in response to IGF is dependent on IGFBP proteases,which induces the effects of IGF [48, 49].

IGF regulates the neointimal of restenosis after coronaryartery injury. The most important role of IGF in restenosisextending includes increasing the proliferation of VSMCsand proteoglycan synthesis [50]. IGF by increasing the ex-pression of αVβ3 integrin, migrating VSMCs from media toneointima, and upregulating the synthesis of tropoelastin (it isrebuilt after the destruction of the elastin layer due to vascularinjury) can induce post-angioplasty restenosis. Research hasshown that tropoelastin accounts for more than 50% of all IGFproteins synthesized in the neointima. Therefore, elastin ex-pression at the transcriptional levels is regulated by IGF func-tion [51]. This factor also contributes to the increased synthe-sis of ECM and plaque growth, which can contribute to neo-intimal hyperplasia [50]. IGF-1 can stimulate endothelial cellmigration and organization; in this way, reduces the integrityof the vascular wall. Besides, IGF-1 induces MQ chemotaxis,LDL uptake excess, and secretion of proinflammatory cyto-kines, which provides the conditions for atherosclerosis andeven ISR [50, 52]. Studies suggest that IGF stimulates thesecretion of proinflammatory cytokines, including TNF-α,which can increase chemotactic MQ migration. Besides, IGFplays a crucial role in the homeostasis of the extracellularmatrix. Indeed, IGF, by stimulating chondrocytes, may beinvolved in the regulation of proteoglycan synthesis [53,54]. The presence of proinflammatory cytokines during theperiod of inflammation that occurs after the damage to thevessel walls can interfere with the balance between synthesisand degradation in IGF. For example, by increasing the induc-tion of IGFBP-3 and IGFBP-5, the secretion of TNF-α, IL-1α, and IL-1β inhibits the proteoglycan synthesis caused byIGF-1 function, thus can reduce the ISR after injury [8]. Inaddition to the effect of proinflammatory cytokines on IGF-1,growth factors such as PDGF can also affect IGF-1 activity.PDGF seems to stimulate c-myc expression. This regulatorgene increases the ability of the IGF-1 receptor to bind toIGF-1; therefore, it can contribute to the development of re-stenosis [55]. Surprisingly, IGFBP-4 plays a role in inhibitingIGF-1 activity. Of course, the inhibitory effect of this receptoris suppressed by IGFBP-4 proteases that have the IGFBP-4cleave property, and IGF-1 can induce its effect on the cell [11,49]. Interestingly, pregnancy-related plasma protein A (PAPP-A) is elevated in people who have a vascular injury after stentimplantation. Studies have shown that PAPP-A can act as anIGF-1 regulator through the proteolysis of IGFBP-4, whichcan cause IGF-1 effects in the cell and ultimately cause neo-intimal hyperplasia. Therefore, PAPP-A in pregnant motherscan be a risk factor and a diagnostic marker to increase thelikelihood of restenosis [27, 48, 56].

Considering the important role of IGF in stimulatingthe proliferation and migration of VSMCs, variousmethods for reducing the effect of this factor can be ap-plied. According to studies conducted on mice models, theIGF-1 analog (stable D-peptide) can inhibit VSMC

�Fig. 1 The simultaneous effects of cytokines and growth factors in thepathogenesis of restenosis. a In the process of inflammation, the secretionof cytokines causes the invasion of inflammatory cells such as MQs,monocytes, and T cells. Monocytes cause proliferation of fibroblasts bysecretion of PDGF. Also, PDGF causes more growth in monocytes. MQswith the secretion of inflammatory cytokines such as TGF-β enhance theperformance of the PDGF, which increases VSMC proliferation and theirmigration to the intima. On the other hand, the simultaneous secretion ofTNF-α and IL-1 with bFGF leads to stimulation of fibroblasts and endo-thelial cells. Endothelial cells through the secretion of the VEGF stimulateproliferation andmigration of VSMCs to the intima, but in the presence ofTGF-β, their function is inhibited. On the other hand, in the presence ofbFGF, fibroblasts are affected by the IFNγ, which increases the ECMaccumulation and provides conditions for inducing restenosis.Meanwhile, the release of TNF-α and IL-1 inhibits the biological functionof the IGFs (which are synthesized in the liver), thus prevents the forma-tion of the intima and reduces restenosis. b The origin of growth factorsand their functional consequences, as well as the primary cells involved inrestenosis, are shown more clearly. Also, the stimulatory or inhibitoryeffects of TNF-α, IL-1, TGF-β, and IFNγ on the cells involved in reste-nosis and growth factor function can be deduced. Abbreviations: TNF-α:tumor necrosis factor-alpha, IL-1: interleukin-1, IFNγ: interferon-gam-ma, PDGF: platelet-derived growth factor, bFGF: basic fibroblast growthfactor, ECM: extracellular matrix, TGF-β: transforming growth factor-beta, EC: endothelial cell, VEGF: vascular endothelial growth factor,VSMC: vascular smooth muscle cells, MQ: macrophage, IGF: insulin-like growth factor

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proliferation through inhibiting IGF-1/IGF-1 receptor in-teraction [55]. Also, the use of long-acting somatostatincan inhibit IGF activity, which is clinically useful in re-ducing restenosis [57, 58]. On the other hand, to preventthe PDFG stimulatory effect on IGF-1, antisense oligonu-cleotides can be used to inhibit c-myc, which is an effec-tive way to reduce neointimal formation [55, 59].Inhibitors of αVβ3 (antagonists) through inhibiting IGF-1 signaling and ECM accumulation can also be used toprevent the migration of VSMCs into the neointimal area[11, 60, 61]. Therefore, understanding the role of IGF andthe effects of other cytokines and growth factors (such asPDGF) can help us in using IGF inhibitors to reduce themigration of VSMCs to the intimal area and to preventrestenosis [8, 50, 55].

VSMCMigration Induced by FGF in Restenosis

FGF is a polypeptide mitogen which acts as a significant pro-liferative agent for endothelial cells and fibroblasts. FGF issecreted by monocytes and binds to heparan sulfate in thebasement membrane of the endothelial cells, which is why itis also known as the heparin-binding growth factor [62, 63].FGF consists of two classes, and the second class has a broadtissue distribution, so is known as the basic fibroblast growthsfactor (bFGF). FGF receptors include both high- and low-affinity forms at the cell surface, but high-affinity receptorsare more pronounced after vascular injury and play a moreimportant role in transmitting FGF signal [64, 65].

FGF can play a role in the migration of endothelial cellsand VSMCs through synthesis and deposition of ECM com-ponents (such as collagen) [66]. FGF often exerts its effect onFGFR-2, which, after binding to it, induces auto-phosphorylation [67]. After vascular injury and stimulationof thrombin and Xa, bFGF binds to the pericellular matrix.In addition to FGFR-1, bFGF activates PDGFR via receptortyrosine kinase (RTK). The activation of PDGFR requiresFGFR-1 transactivation, which ultimately causes the prolifer-ation of VSMCs [68]. One of the differences between bFGFand PDGF is that the latter is directly involved in the SMCmigration via chemotactic stimulus, while the former inducesits effects directly. Therefore, the stimulatory effect of bFGF ishigher than that of PDGF, and it has more potential in reste-nosis extension [66, 67]. After stent implantation and vascularinjury–induced inflammation, secretion of some inflammatorycytokines can enhance the effects of the bFGF. For instance,secretion of IL-1 and TNF-α can increase collagen synthesisand stimulate fibroblast proliferation, thereby enhancing theeffects of bFGF [69, 70]. On the other hand, the secretion ofIFNγ from T cells, in addition to regulating the secretion ofgrowth factors, directly stimulates fibroblast growth. Also, inthe inflammatory lesion, T cells secrete fibroblast-activating

factor (FAF) which the main property of that is stimulatingfibroblast proliferation and inducing neointimal hyperplasia[70, 71]. Various factors such as phosphorylation in RTK orregulation in the actins (in the cytoskeleton) can stimulateVSMC migration by bFGF [72, 73]. The migration mecha-nism of VSMCs is due to the launch of intracellular pathways,including reactive oxygen species (ROS). The most importantof ROS source in the vascular system is provided via NADPHoxidases, which contribute to the formation of NOX1, NOX2,and NOX4 (cytosolic components) [74]. After activating theNOX1 by bFGF, the ROS pathway and, eventually, SMCmigration are stimulated [67].

To reduce the effects of bFGF and prevent restenosis, tetra-methoxyphenyl porphyrin (TMPP) (bFGF analog) can beused [75]. TMPP directly binds to bFGF and FGFR with highaffinity, which can be competitively inhibited by heparin.TMPP blocks the interaction between bFGF and FGFR in aheparin-dependent manner and acts as anti-mitogenic to pre-vent SMC proliferation. Also, the appropriate dose of TMPPcan prevent VEGF binding to its own RTK, which is useful inreducing intimal hyperplasia [76, 77]. Besides, PPARγ ago-nis t s inh ib i t bFGF- induced DNA synthes is andchemoattractant effect of PDGF [78]. Overall FGF, along withinflammatory cytokines such as IL-1, TNF-α, and IFNγ, canplay an essential role in the proliferation of fibroblasts andVSMC as well as VMSC migration, indicating the coopera-tion of FGF and inflammatory cytokines in increasing thelikelihood of restenosis [68, 69, 71]. The use of bFGF analogsand bFGF inhibitors can reduce the probability of ISR [77].

VEGF as a Double-Function Growth Factorin Restenosis

VEGF is another growth factor that is produced at the site ofthe stent; due to the activity of PDGF and FGF and along withinflammatory cytokines, it affects the migration and prolifer-ation of VSMCs [9]. VEGF is an essential regulator of angio-genesis and skeletal growth produced by vascular endotheli-um [79]. The biological function of VEGF is regulated byRTKs at the cell surface, including VEGFR-1 and VEGFR-2[80].

After stenting, the arterial wall is almost empty of endothe-lial cells, and consequently, endothelium loss induces VSMCproliferation because endothelium activity leads to inhibitionof VSMChyperplasia [9]. VEGF promotes the integration andregeneration of endothelium, in this regard, act as an inhibitorfor VSMC proliferation; thus, it may be useful in reducingrestenosis [9, 81, 82]. Also, studies show that vascular injuryitself leads to the expression of TGFβ (secreted by endothelialcells), which is involved in the regulation of VSMC prolifer-ation [25]. On the other hand, VEGF, along with PDGF,causes downregulation in the expression of TGFβ but

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increases the expression of bFGF [10]. Therefore, it can beargued that VEGF, along with PDGF, indirectly plays a role indecreasing the migration and proliferation of VSMCs throughincreasing the expression of bFGF and decreasing the expres-sion of TGFβ expression. This issue shows the double role ofVEGF about restenosis [83]. VEGF singly has an inhibitoryeffect onVSMCproliferation, which reduces restenosis, but inthe presence of inflammatory cytokines such as TGFβ, mostof VEGF effect is devoted to reducing the expression of thesecytokines, which indirectly increases the proliferation ofVSMCs and their migration to the intimal area. Therefore,inflammatory cytokines can enhance VEGF function to in-duce restenosis [83–85]. Genetically, studies have shown that,in people who have a homozygous A allele in the Mannose-binding lectin-2 gene, serum levels of VEGF and PDGF areelevated after stent implantation. Therefore, this genotype canbe considered as a predisposing factor for ISR. Measuringserum levels of VEGF and PDGF after stent implantationcan be a prognostic marker for the diagnosis and severity ofrestenosis [86–88].

Given the fact that drug-eluting stent (DES) is more effec-tive than bare-metal stents, the anti-VSMC proliferation prop-erties of VEGF can be used in restenosis suppression [89, 90].VEGF plays an important role in revascularization and re-endothelialization by stimulating migration and maturationin endothelial progenitor cells (EPCs); this can also be usedin the field of endothelial gene therapy [91]. Similarly, the co-operation of VEGF and paclitaxel (PTX), a type of mitotic

inhibitor, can be used to suppress restenosis. To achieve thisgoal, a DES polymer can be designed with anti-inflammatoryproperties in which poly lactic-co-glycolic acid (PLGA) isused and contains VEGF DNA plasmid in the outer layerand PTX in the inner core region. Thus, the VEGF/PTX coat-ed stent through an automatic spray machine is located on themetal stent. Due to the re-endothelialization and revasculari-zation properties of VEGF, and the anti-VSMC proliferationproperties of PTX, it induces endothelial healing, reducesVSMCproliferation, and eventually suppresses the neointimalhyperplasia [92–95]. Therefore, although VEGF can decreaseVSMC proliferation and inhibit restenosis singly, in the pres-ence of inflammatory cytokines, it increases the proliferationof VSMCs and their migration to the intimal region [83]. Also,the revascularization and re-endothelialization properties ofVEGF can be used in the VEGF/PTX coated stent to inhibitthe process of restenosis [86, 93, 96]. The effects of the mostimportant inflammatory cytokines on the growth factors in-volved in restenosis, as well as several restenosis inhibitors,are summarized in Table 1.

Discussion

It seems that after stent-induced vascular injury, inflammatoryactivation and inflammatory growth factors are the most crit-ical factors in the neointimal formation and migration ofVSMCs to the intimal region (Fig. 1) [3, 97]. Recruitment of

Table 1 Effect of growth factors induced by inflammatory cytokines on cellular functions that are involved in restenosis

Growth factors Source of growth factors Function TGF-β IL-1 TNF-α Restenosis inhibitors Ref.

PDGF MQsPlateletsMonocytesInflammatory cells

➢ SMC proliferation➢ Fibroblast proliferation➢ MQ recruitment➢ EC proliferation

+ 0 0 • AG1295• Imatinib mesylate• Anti-PDGF Ig• Type II protein kinase inhibitors• TAK-733

[12, 21, 36–39]

IGF Liver cells ➢ SMC proliferation➢ EC proliferation➢ ECM accumulation➢ MQ chemotaxis➢ Proteoglycan synthesis➢ Tropoelastin synthesis

0 _ _ • IGF-1 analog (stable D-peptide)• PPARγ-agonists• Somatostatins• αVβ3 inhibitors

[8, 45, 47, 49, 53]

bFGF Monocytes ➢ SMC proliferation➢ Fibroblast proliferation➢ EC proliferation➢ ECM accumulation➢ PDGFR activation

+ + + • bFGF analog (TMPP) [58, 60–62, 70]

VEGF Vascular endothelium ➢ EC proliferation➢ Revascularization➢ Re-endothelialization

_ 0 0 • VEGF/PTX [74–77, 85–87]

PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor;SMC, smooth muscle cell;MQ, macrophages; EC, endothelial cell; ECM, extracellular matrix; TGF-β, transforming growth factor-beta; IL-1, interlukin-1; TNF-α, tumor necrosis factor-alpha; Ig, immunoglobulin; TMPP, tetra-methoxyphenyl porphyrin; PTX, paclitaxel

(+) = stimulates activity/(−) = inhibits activity/(0) = depends on the presence of other cytokines

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the inflammatory cells to the site of injury can be involved incausing in ISR [4]. Following vascular injury, the overexpres-sion of adhesion molecules (such as glycoprotein Ilb/IIIaintegrin) and the secretion of inflammatory cytokines (suchas TGFβ which acts as a migratory factor) lead to recruitmentof monocytes and increased FGF secretion. This double-sidedcollaboration, by affecting the RTKs (present in FGFR-1),stimulates platelet activation, PDGF secretion, collagen/proteoglycan synthesis, and ECM accumulation, which canlead to intimal hyperplasia [98]. With the activation ofPDGF, VEGF secretion increases in monocytes, which canenhance endothelial integrity through revascularization andre-endothelialization and prevent the proliferation ofVSMCs, and thus be involved in controlling restenosis [9].In the meantime, secretion of some inflammatory cytokinescan alter the function of VEGF, increasing the proliferationand migration of VSMCs at the site of the injury. In responseto the increased inflammation of TGFβ, endothelial cells in-crease VEGF secretion, which has an inhibitory effect onTGFβ, and by increasing the expression of bFGF, it can leadto the migration of VSMCs to the intimal region [83, 85]. Inaddition, in the initial phase of inflammation, degranulation ofplatelets resul ts in the release of PDGF, TGFβ ,thrombospondin, and factor epidermal growth (EGF) (thatplay a role in the rapid recruitment of IGF-1 and TGF-α),which have synergism effects for other inflammatory growthfactors [63, 99, 100]. In addition to affecting growth factors,probably the simultaneous secretion of inflammatory cyto-kines can contribute to stimulating or inhibiting ECM compo-nents, chemokines, and other cytokines. For example, IL-18by activating intracellular pathways such as mitogen-activatedprotein kinases (MAPKs), as well as activating transcriptionfactors such as NF-kB and AP-1, can increase the expressionof IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) (involved in recruiting inflammatory cells to the site ofinflammation). All the mechanisms and functions mentionedabove contribute to VSMC proliferation and increase the like-lihood of restenosis [101, 102].

Recently, biological studies of ISR have shown that NF-kB/p65 pathway plays a significant role in the overexpressionof VCAM-1 and E-selectin following stent implantation[103]. In human studies, it was found that, following a de-crease in NF-kB/p65 translocation, the expression ofVCAM-1, E-selectin, and endothelial cell activation also di-minished dramatically. Therefore, a reduced NF-kB/p65 path-way can be one of the valuable therapeutic targets to preventthe progression of ISR [104]. Studies show that among thevarious risk factors contributing to ISR, the role of genetics isvery prominent. Genetic polymorphisms associated withgrowth factors and inflammatory cytokines nowadays are con-sidered as one of the most critical risk factors of ISR. Forinstance, it has been proved genotypes A/A for VEGF-A, C/C for PDGF-B, and A/A for TGF-B1 are associated with an

increased risk of ISR [105]. Alongside these genetic risk fac-tors, polymorphisms in the gene encoding IL-6 or the presenceof homozygous allele A in the MBL-2 gene, which are usefulin inducing inflammatory and VEGF effects, can be consid-ered as genetic risk factors for restenosis due to inducingVSMC proliferation [15, 86, 87, 106]. On the other hand, ithas been observed that increased serum levels of inflammato-ry factors, growth factors, and adhesion molecules such asCRP, P-selectin, IL-18, IL-6, IL-8, PDGF, and bFGF have adiagnostic and prognostic value in patients who require stentimplantation [18, 96]. Today, genetic studies have a specialinterest in the role of prognostic and diagnostic microRNAs(miRs) in cells [107]. Studies have demonstrated that miRs viaregulating vascular cellular events and modulating the expres-sion of their target genes play important roles in restenosisinduction. Levels of circulating miRs such as miR-145 andmiR-143 in patients with ISR are associated with increasedoccurrence of ISR and can use as novel biomarkers for ISR[90]. To prevent restenosis, antagonists and protein kinaseinhibitors can be used to control the effects of growth factors[11, 12]. Anti-inflammatory proteins, recombinant antibodies,and anti-selectins can also be used to reduce the synergismeffects of inflammatory cytokines [15, 22]. Therefore, it canbe argued that inflammatory cytokines by affecting growthfactors and adhesion molecules may increase the likelihoodof ISR. Therefore, it is suggested that the measurement ofinflammatory factors alongside growth factors in initial in-flammation in patients with ISR following vascular injuryhas prognostic and therapeutic values.

Acknowledgments We wish to thank all our colleagues in Allied HealthSciences School, Ahvaz Jundishapur University of Medical Sciences.

Authors’ ContributionsN.S. conceived the manuscript and revised it. M.M., N.A, H.H, and

M.M. wrote the manuscript and prepared the table and figure.

Compliance with Ethical Standards

Research Involving Human Participants and/or Animals This articledoes not contain any studies with human participants or animals per-formed by any of.

Conflict of Interest The authors declare that they have no conflict ofinterest.

Informed Consent For this type of study, informed consent is notrequired.

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