**8. Prevention of in-stent restenosis via other biomolecules and peptides**

After coronary artery angioplasty (PCI, heart stent surgery), several biomolecules participate in formation of cellular response. Leucocytes and thrombosites discharge cytokines and growth factors inside the blood vessel, adventitia, and encompassing tissue after blood vessel damage. It is well known that tumor necrosis factor α (TNF-α), platelet-derived growth factor (PDGF), and transforming growth factor β (TGF-β) modulate cellular behaviors. Following the activation and proliferation of smooth muscle cell by fibroblasts, significant cumulation and response of extracellular matrix (ECM) in the vessel wall occur. Due to the responsibilities in cellular interactions, ECM, the active component of the vessel wall, is known as a considerable player in vascular diseases. The ECM consists of a diversity of molecules, including collagen, elastin, glycoproteins, and proteoglycans.

Type III collagen is the most abundant matrix protein in a muscular coronary artery. MMPs move through and interact with the C-terminus of the collagen molecule. Several MMPs attend in the collagen degradation mechanism. Interstitial collagenases (MMP1, MMP8, and MMP13) are the most prevalent MMPs that cleave fibrillar collagens, while gelatinases are active against nonfibrillar collagen components of the ECM.

While some of the cytokines and growth factors such as uPA, MT-MMPs, IL-1, PDGF, and TNF-α arrange MMP activation, TGF-β, heparin, steroids, and tissue inhibitor of metallopro‐ teinases (TIMP 1-4) inhibit MMP activity.

Besides, the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are also another biomolecule group related with atherosclerosis and possibly restenosis. Protease family ADAMTS enzymes regulate ECM transformation by reducing versican (VCAN—a large extracellular matrix proteoglycan) and procollagen-type matrix components. The degradation of versican by ADAMTS-1 catalyses the migration of SMCs and intimal hyper‐ plasia. Also, ADAMTS-7 enables SMC migration and intimal thickening by degradation of cartilage oligomeric matrix protein (COMP). ADAMTS [2, 3, and 14] involve in the removal of N-terminal peptides from procollagen to form mature collagen. Due to their substrate specificity, ADAMTS enzymes are considered as attractive pharmaceutical targets.

Devices having biomimetic surfaces coated with sequences of extracellular matrix proteins, peptides, and enzymes could accelerate endothelial regeneration and prevent from both the thrombic and proliferative effect after stent implantation. In around 25% of patients, th e development of scar tissue underneath the covering of the course may be thick to the point that it can block the bloodstream and produce a vital blockage. At the point when a stent is set in a vein, new tissue becomes inside the stent, covering the struts of the stent. At first, this new tissue comprises healthy cells to cover the blood vessel endothelium. This is a great impact in light of the fact that the improvement of typical covering over the stent permits blood to stream easily over the stented territory without coagulating. Later, scar tissue may structure under‐ neath the new healthy coating [32].

(miRNA, siRNA, plasmid, peptide, etc.), different types of materials and different types of vector systems are used. Therefore, it is important to develop unique gene delivery systems

**8. Prevention of in-stent restenosis via other biomolecules and peptides**

After coronary artery angioplasty (PCI, heart stent surgery), several biomolecules participate in formation of cellular response. Leucocytes and thrombosites discharge cytokines and growth factors inside the blood vessel, adventitia, and encompassing tissue after blood vessel damage. It is well known that tumor necrosis factor α (TNF-α), platelet-derived growth factor (PDGF), and transforming growth factor β (TGF-β) modulate cellular behaviors. Following the activation and proliferation of smooth muscle cell by fibroblasts, significant cumulation and response of extracellular matrix (ECM) in the vessel wall occur. Due to the responsibilities in cellular interactions, ECM, the active component of the vessel wall, is known as a considerable player in vascular diseases. The ECM consists of a diversity of molecules, including collagen,

Type III collagen is the most abundant matrix protein in a muscular coronary artery. MMPs move through and interact with the C-terminus of the collagen molecule. Several MMPs attend in the collagen degradation mechanism. Interstitial collagenases (MMP1, MMP8, and MMP13) are the most prevalent MMPs that cleave fibrillar collagens, while gelatinases are active against

While some of the cytokines and growth factors such as uPA, MT-MMPs, IL-1, PDGF, and TNF-α arrange MMP activation, TGF-β, heparin, steroids, and tissue inhibitor of metallopro‐

Besides, the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are also another biomolecule group related with atherosclerosis and possibly restenosis. Protease family ADAMTS enzymes regulate ECM transformation by reducing versican (VCAN—a large extracellular matrix proteoglycan) and procollagen-type matrix components. The degradation of versican by ADAMTS-1 catalyses the migration of SMCs and intimal hyper‐ plasia. Also, ADAMTS-7 enables SMC migration and intimal thickening by degradation of cartilage oligomeric matrix protein (COMP). ADAMTS [2, 3, and 14] involve in the removal of N-terminal peptides from procollagen to form mature collagen. Due to their substrate

Devices having biomimetic surfaces coated with sequences of extracellular matrix proteins, peptides, and enzymes could accelerate endothelial regeneration and prevent from both the thrombic and proliferative effect after stent implantation. In around 25% of patients, th e development of scar tissue underneath the covering of the course may be thick to the point that it can block the bloodstream and produce a vital blockage. At the point when a stent is set in a vein, new tissue becomes inside the stent, covering the struts of the stent. At first, this new tissue comprises healthy cells to cover the blood vessel endothelium. This is a great impact in

specificity, ADAMTS enzymes are considered as attractive pharmaceutical targets.

that have enhanced transgene efficacy, are safe, and are clinically reliable.

elastin, glycoproteins, and proteoglycans.

424 Muscle Cell and Tissue

nonfibrillar collagen components of the ECM.

teinases (TIMP 1-4) inhibit MMP activity.

Due to the mechanisms of restenosis after angioplasty operation, it is known that TGF-β increases. Yamamoto et al. [33] studied on ribozymes to inhibit TGF-β by cleaving the targeted gene. TGF-β gene demonstrates 100% homology among the human, rodent, and mouse species. They built ribozyme oligonucleotides targeted to the sequence of the TGF-β gene and used it in a rat balloon injury model. Ribozyme inhibits TGF-β mRNA in cultured VSMCs, and using ribozyme oligonucleotides, TGF-β was inhibited, resulting in a significant reduction in neointimal formation in a rat balloon injury model. They also modified ribozyme oligonu‐ cleotides containing phosphorothioate DNA and RNA targeted to the TGF-β gene. TGF-β expression was decreased with modified ribozyme oligonucleotides. It was shown that the selective blockade of TGF-β resulted in the inhibition of neointimal formation and reduction in collagen synthesis. It was assumed that the modification of ribozyme oligonucleotide pharmacokinetics would create potential therapeutic strategy for the treatment of cardiovas‐ cular disease related to high TGF-β.

Merrilees and colleagues [34] mentioned the importance of viscoelastic properties of vessel wall. They concentrated on arterial matrix proteoglycans, which are related to increasing tissue volume and atherogenicity. One of the basic stimulants of proteoglycans is transforming growth factor β1 (TGF-β1). The aim of the researchers was to investigate the effects of dimin‐ ishing TGF-β1 and proteoglycan synthesis in vivo. They used rabbit with balloon catheter damage treated with a TGF-β1 antisense phosphorothioate oligonucleotide connected in a pluronic gel to the adventitia. Statistical information showed that intimal thickening and proteoglycan synthesis were inhibited with the inhibition of TGF-β1antisense. These data affirm a part for TGF-β1 in creating neointima and exhibit a particular impact on the combi‐ nation, appropriation, and gathering of proteoglycan matrix.

There has been extraordinary enthusiasm for the way of stents themselves and the methods used to embed them as boosts for in-stent restenosis. Stent design, arrangement, length, and measures of coronary stream have gotten significant consideration. Additionally, there has been incredible enthusiasm for the stents coated with gradually eluting antirestenotic special‐ ists. The use of drug-eluting stents limits neointima hyperplasia. Pyrrole-imidazole (PI) polyamide targeting TGF-β1 is one of the candidate agents for the drug-eluting stents. In one study, the effects of PI polyamide targeting the TGF-β1 promoter in rat after balloon injury were studied. PI polyamide was designed to connect with the TGF-β1 promoter and carried out for 10 min after inducing balloon injury. Neointimal thickening and re-endothelialization were analyzed [35]. TGF-β1 was significantly decreased with PI polyamide, targeting the expression of TGF-β1 mRNA. Fibronectin and collagen were also affected after targeting. It was understood from the research that synthetic PI polyamide has potential to extinguish neointimal hyperplasia after arterial injury. It was assumed from the article that PI polyamide targeting TGF-β1 could be coated on the stent for the prevention of in-stent restenosis as nextgeneration drug-eluting stents [35]. Besides, the long-term benefit and safety of coated active stents are crucial research field and should be examined extensively in further studies. The application of prohealing substances and antirestenosis drugs together as coated on stent represents a diversified approach to reduce restenosis without an increased risk for stent thrombosis [36].

The prevention of new techniques of in-stent restenosis such as peptide-loaded stents to inhibit the biological reactions of the vessel wall gains greater importance in novel studies.

According to the previous studies in the 90s, it was found that fibrin-coated stents lessened thrombogenicity. Baker et al. [37] loaded RGD peptide into fibrin-coated stents due to the inhibition effect of RGD peptide on interaction between fibrinogen with platelets. They have used those stents in an atherosclerotic rabbit model. Four weeks after stent implantation, myointimal hyperplasia in coated and uncoated stent groups were measured and it was seen from the analysis that the extension of myointimal hyperplasia in coated stent group was lower than in the uncoated stent group. Vessel cross-sectional areas of coated stents also were lesser than the uncoated stents. As a result, it was thought that RGD-loaded fibrin-coated stents have prevented vascular complications after stent implantation.

Hong et al. [38] have estimated the advantage and controlling of angiopeptin in a porcine coronary in-stent restenosis model. They have used forty pigs arranged in four groups in the experiments. Out of the control group, the other three groups were treated respectively with one-time treatment (200 µg angiopeptin) at the site of stent placement, continuous angiopeptin over a 1-week period via a subcutaneous osmotic pump (200 µg/kg total dose), and combina‐ tion of both locally and systematically. In conclusion, this study has demonstrated that the group applied with continuous subcutaneous treatment with angiopeptin after stent implan‐ tation significantly has reduced in-stent restenosis by inhibiting neointimal hyperplasia.

In 1999, a synthetic octapeptide, angiopeptin, was used to inhibit tissue response against growth factor, insulin-like growth factor, and interleukin-1-mediated endothelial cell adhesion.

Wiktor brand stents were coated with polyorganophosphazene. Researchers loaded angio‐ peptin into that biodegradable polymer and implanted the stent in porcine coronary arteries. The group has indicated that angiopeptin increased lumen diameter and morphometric lumen area in significantly as a percentage [39].

We can observe several studies in stent implantation area about local biomolecule delivery made since 1999. Coating of stent is necessary for carrying, prolongation, and elution of the drug through the targeted area effectively and without any loss arising from catheter. Studies on physical strengths of polymers coated on stents and eliciting inflammatory reactions occurring after operation are still ongoing. A portion of the presently accessible gadgets, coatings, and stents are drawing near to making this point an achievable reality. Stent thrombosis remains an important problem after the implantation of different stent types. Coating of stents impacts thrombogenicity. Simple chemical coating lessens platelet adhesion, fibrinogen binding, and effectual against in-stent restenosis in clinical trials. Fuchs et al. [40] were also interested in solving this problem about thrombosis with vasoactive agents. They studied on in vitro and in vivo effects of C-type natriuretic peptide (CNP) that has dual effects on different cell types in a porcine restenotic model. Although gene transfer of CNP in cultures of porcine vascular cells had achieved 30% reduction of growth of SMCs, the suppression of endothelial growth using CNP had failed. Usage of the CNP gene could be a solution for compress formation of restenosis while preventing late thrombosis [40].

application of prohealing substances and antirestenosis drugs together as coated on stent represents a diversified approach to reduce restenosis without an increased risk for stent

The prevention of new techniques of in-stent restenosis such as peptide-loaded stents to inhibit

According to the previous studies in the 90s, it was found that fibrin-coated stents lessened thrombogenicity. Baker et al. [37] loaded RGD peptide into fibrin-coated stents due to the inhibition effect of RGD peptide on interaction between fibrinogen with platelets. They have used those stents in an atherosclerotic rabbit model. Four weeks after stent implantation, myointimal hyperplasia in coated and uncoated stent groups were measured and it was seen from the analysis that the extension of myointimal hyperplasia in coated stent group was lower than in the uncoated stent group. Vessel cross-sectional areas of coated stents also were lesser than the uncoated stents. As a result, it was thought that RGD-loaded fibrin-coated stents have

Hong et al. [38] have estimated the advantage and controlling of angiopeptin in a porcine coronary in-stent restenosis model. They have used forty pigs arranged in four groups in the experiments. Out of the control group, the other three groups were treated respectively with one-time treatment (200 µg angiopeptin) at the site of stent placement, continuous angiopeptin over a 1-week period via a subcutaneous osmotic pump (200 µg/kg total dose), and combina‐ tion of both locally and systematically. In conclusion, this study has demonstrated that the group applied with continuous subcutaneous treatment with angiopeptin after stent implan‐ tation significantly has reduced in-stent restenosis by inhibiting neointimal hyperplasia.

In 1999, a synthetic octapeptide, angiopeptin, was used to inhibit tissue response against growth factor, insulin-like growth factor, and interleukin-1-mediated endothelial cell

Wiktor brand stents were coated with polyorganophosphazene. Researchers loaded angio‐ peptin into that biodegradable polymer and implanted the stent in porcine coronary arteries. The group has indicated that angiopeptin increased lumen diameter and morphometric lumen

We can observe several studies in stent implantation area about local biomolecule delivery made since 1999. Coating of stent is necessary for carrying, prolongation, and elution of the drug through the targeted area effectively and without any loss arising from catheter. Studies on physical strengths of polymers coated on stents and eliciting inflammatory reactions occurring after operation are still ongoing. A portion of the presently accessible gadgets, coatings, and stents are drawing near to making this point an achievable reality. Stent thrombosis remains an important problem after the implantation of different stent types. Coating of stents impacts thrombogenicity. Simple chemical coating lessens platelet adhesion, fibrinogen binding, and effectual against in-stent restenosis in clinical trials. Fuchs et al. [40] were also interested in solving this problem about thrombosis with vasoactive agents. They studied on in vitro and in vivo effects of C-type natriuretic peptide (CNP) that has dual effects on different cell types in a porcine restenotic model. Although gene transfer of CNP in cultures

the biological reactions of the vessel wall gains greater importance in novel studies.

prevented vascular complications after stent implantation.

thrombosis [36].

426 Muscle Cell and Tissue

adhesion.

area in significantly as a percentage [39].

Recent evidence point out endocrine activities are mediated by growth hormone. Shu and colleagues made studies on Ghrelin, a 28-amino acid peptide, which had been isolated from both human and rat stomach that was mediated by growth hormone secretagogue receptor. Ghrelin is expressed in stomach tissue and has several important physiological effects in secretion of growth hormone, inflammation, cell proliferation, differentiation, and apoptosis. Besides, it has wide role on cardiovascular system, such as increasing myocardial contractility, improving cardiac function, inhibiting ventricular remodeling, and attenuating cardiac ischemia-reperfusion injury. Novel studies indicated inhibition of ghrelin on vascular inflam‐ mation and proliferation of VSMCs. It also repairs endothelial cells, promotes vascular endothelial function, inhibits platelet aggregation, and exerts antithrombotic effects. Volante et al. [41] had found its protective effect on vascular endothelial function by increasing endothelial nitric oxide synthase (eNOS) expression and improving endothelial function.

Another research group has also stated that ghrelin has prevention against platelet aggrega‐ tion, MCP-1 expression, and exerts antithrombotic effects. Consequently, ghrelin is considered as therapeutic candidate for the prevention and treatment of ISR [42].

In the 2000s, subjects on expanded polytetrafluoroethylene-covered stent-graft have been carried out. Hamm et al. [43] have used 15-amino acid peptide (P-15), which had cell adhesion property in supporting the endothelization on inner surface after implantation. The recovery of a utilitarian endothelium over the surfaces of the embedded gadgets may restrain both the thrombotic and proliferative reaction after gadget implantation. It was discovered from studies that matrix proteins such as collagen and laminin could improve and increase endothelial regeneration. Starting from this idea, P-15 synthetic peptide, which had cell binding cell of collagen [44], has been tried in in vitro studies with endothelial cells [45]. It was shown that cell migration and adhesion had increased on P-15-coated surface. According to those experiments, P-15 peptide-coated stents had been used in clinical applications. P-15 peptidecoated stents had demonstrated that similar healing with uncoated stents had provided high luminal support and protected from distal emboli. Based on the results from this preparatory, it was figured out that a peptide-treated stent is an alluring methodology for the treatment of stenosed saphenous vein grafts [43].

A different approach with angiotensin-[1-7], an endogenous, biologically active peptide, has come from Langeveld et al. [46]. Angiotensin-[1-7] is a part of the renin-angiotensin system, which has vasodilatory, antithrombotic, and antiproliferative properties. The effects of angiotensin-[1-7] infusion on neointimal formation after stent placement in male Wistar rats have been investigated in this study. Other than the control group, angiotensin-[1-7] [24 g/kg per hour) had been given to rats that underwent stent implantation in the abdominal aorta or sham surgery by placing an osmotic minipump. The endothelial function has been measured in isolated thoracic aortic rings after 4 weeks by histomorphometric and histological analyses. Researchers have found out that angiotensin-[1-7]-treated group has exhibited a significant decrease in neointimal thickness, neointimal area, and percentage stenosis compared with the control group [46]. Results have showed that angiotensin-[1-7] treatment has reduced neoin‐ timal formation after stent implantation in rats. This consequence has supported the idea of Ang-[1-7] could be an alternative to the presently available aggressive antiproliferative drugloaded stents [46].

Yu et al. [47] were interested in calcineurin/nuclear factor of activated T cells (NFAT) axis. It plays an important role in VSMCs that inhibits NFAT. In earlier studies, the main epitope site on NFAT for calcineurin was discovered. The optimization of this site had induced to the exploration of synthetic peptide VIVIT. Yu et al. [47] have used VIVIT to examine the inhibition NFAT activation and NFAT-mediated proliferation and inflammation in RAW 264.7 macro‐ phages, Ea.Hy.926 endothelial cells and VSMCs, and blocked ionomycin-elicited nuclear import of NFAT. It was also found that VIVIT suppressed platelet-derived growth factor-BB (PDGF-BB) and thrombin induced VSMC proliferation. According to the data, it was reported that NFAT is a regulator of PDGF-BB induced vSMC proliferation. This study stents coated with VIVIT could be a candidate to more specific approaches in the antirestenosis therapy.

In parallel with the ongoing experiments, integrin-binding cyclic Arg-Gly-Asp peptide (cRGD)-loaded stents were used to bound coronary neointima formation and to increase endothelialization by attracting endothelial progenitor cells. It has been stated again that stent coating with cRGD may be useful for reducing in-stent restenosis by accelerating endotheli‐ alization [48]. Another study was about RGD-modified liposomes targeted to integrin GPIIbeIIIa on activated platelets [49]. RGD-conjugated liposomes have also been tested in vivo in a rat carotid injury model. As seen from the experiments, cyclic RGD liposomes have binded activated platelets significantly higher compared to linear RGD liposomes. Huang et al. [49] have found an approach on optimization of platelet-targeting ability of ligand-modified liposomes. It has been thought to be a solution for sensitive and selective delivery of thera‐ peutic agents in cardiovascular diseases such as atherosclerosis, thrombosis, and restenosis where activated platelets play significant role in disease development, progression, and outcome.

In-stent restenosis is a pathobiologic methodology, histologically different from restenosis after balloon angioplasty and embodied generally of neointima arrangement. Since percuta‐ neous coronary mediation progressively includes the utilization of stents, in-stent restenosis is moreover getting to be correspondingly more regular. Novel applicable and therapeutic approaches in humans for re-endothelialization are about coating of stents with some sub‐ stances to give acceleration for the formation of endothelial coverage safely. It was indicated in a porcine model study that cRGD-coated stents expedite endothelialization [50].

In a novel study, it has been focused on the binding ratio of integrin receptor to subendothelial matrix proteins. When integrin binds to arginine-glycine-aspartic acid (RGD) peptide, it imitates naturally occurring adherent interactions. The surface modification of stents with RGD peptide also contributes selectivity for integrin alpha V beta 3, which stimulates endo‐ thelialization after stent implantation. Joner and colleagues [51] studied on the availability of RGD peptide-loaded titanium-oxide nitinol stents. Functionality of the engrafted RGD peptide has been examined by in vitro endothelial bioassays, and a subsequent 7-day in vivo endo‐ thelialization has been studied by using cRGD-coated self-expanding nitinol stents in rabbits. Significant increase in endothelial coverage with cRGD stent implants has been stated. This study has represented as an innovative strategy to improve endothelialization and to catalyze vascular healing after stent implantation [51].

control group [46]. Results have showed that angiotensin-[1-7] treatment has reduced neoin‐ timal formation after stent implantation in rats. This consequence has supported the idea of Ang-[1-7] could be an alternative to the presently available aggressive antiproliferative drug-

Yu et al. [47] were interested in calcineurin/nuclear factor of activated T cells (NFAT) axis. It plays an important role in VSMCs that inhibits NFAT. In earlier studies, the main epitope site on NFAT for calcineurin was discovered. The optimization of this site had induced to the exploration of synthetic peptide VIVIT. Yu et al. [47] have used VIVIT to examine the inhibition NFAT activation and NFAT-mediated proliferation and inflammation in RAW 264.7 macro‐ phages, Ea.Hy.926 endothelial cells and VSMCs, and blocked ionomycin-elicited nuclear import of NFAT. It was also found that VIVIT suppressed platelet-derived growth factor-BB (PDGF-BB) and thrombin induced VSMC proliferation. According to the data, it was reported that NFAT is a regulator of PDGF-BB induced vSMC proliferation. This study stents coated with VIVIT could be a candidate to more specific approaches in the antirestenosis therapy. In parallel with the ongoing experiments, integrin-binding cyclic Arg-Gly-Asp peptide (cRGD)-loaded stents were used to bound coronary neointima formation and to increase endothelialization by attracting endothelial progenitor cells. It has been stated again that stent coating with cRGD may be useful for reducing in-stent restenosis by accelerating endotheli‐ alization [48]. Another study was about RGD-modified liposomes targeted to integrin GPIIbeIIIa on activated platelets [49]. RGD-conjugated liposomes have also been tested in vivo in a rat carotid injury model. As seen from the experiments, cyclic RGD liposomes have binded activated platelets significantly higher compared to linear RGD liposomes. Huang et al. [49] have found an approach on optimization of platelet-targeting ability of ligand-modified liposomes. It has been thought to be a solution for sensitive and selective delivery of thera‐ peutic agents in cardiovascular diseases such as atherosclerosis, thrombosis, and restenosis where activated platelets play significant role in disease development, progression, and

In-stent restenosis is a pathobiologic methodology, histologically different from restenosis after balloon angioplasty and embodied generally of neointima arrangement. Since percuta‐ neous coronary mediation progressively includes the utilization of stents, in-stent restenosis is moreover getting to be correspondingly more regular. Novel applicable and therapeutic approaches in humans for re-endothelialization are about coating of stents with some sub‐ stances to give acceleration for the formation of endothelial coverage safely. It was indicated

In a novel study, it has been focused on the binding ratio of integrin receptor to subendothelial matrix proteins. When integrin binds to arginine-glycine-aspartic acid (RGD) peptide, it imitates naturally occurring adherent interactions. The surface modification of stents with RGD peptide also contributes selectivity for integrin alpha V beta 3, which stimulates endo‐ thelialization after stent implantation. Joner and colleagues [51] studied on the availability of RGD peptide-loaded titanium-oxide nitinol stents. Functionality of the engrafted RGD peptide has been examined by in vitro endothelial bioassays, and a subsequent 7-day in vivo endo‐ thelialization has been studied by using cRGD-coated self-expanding nitinol stents in rabbits.

in a porcine model study that cRGD-coated stents expedite endothelialization [50].

loaded stents [46].

428 Muscle Cell and Tissue

outcome.

Besides, Kramer et al. [52] insisted on interventional cardiology was revolutionized by stent implantation. Stents were developed with antiplatelet therapy and new materials. They have defended the importance of oral drug usage with newly developed stents together. Angio‐ tensin II (Ang II) is an important vasoactive peptide associated with in-stent restenosis, which is produced locally from vessel wall. Due to the Ang II AT1 receptors' effects on relationship of Ang II with growth and inflammatory signals, A T1-receptor blocking drugs are widely used to treat hypertension and heart failure [53]. Experimental clinical trials has estimated the effect of AT1-receptor blockers on ISR but no significant result was obtained from patients who were treated with drugs [52].

Different treatment about the movement, growth, and adhesion of endothelial cells has been tried to improve the re-endothelization of stents. Yin and colleagues [54] had synthesized muscle adhesive polypeptide mimics including dihydroxyphenylalanine and l-lysine (MAPDL). They had attached MAPDL on ethylene vinyl acetate (EVA)-coated stent with different molecular weight PEG spacers to find out optimum cell bioactivity. According to in vitro analysis, endothelial cells layer formation had significantly increased on the MAPDL-EVA-coated stents in contrast with the control bare stent. In this manner, it was demonstrated that MAPDL-coated EVA surface had decrease platelet adhesion and appeared to be promising solution for re-endothelialization of intravascular stent devices.

As is seen from the experiments, metal-based stents are mostly preferred for coronary artery disease. The recovery of endothelium around the lesion site can be achieved by coating stents with bioactive molecules. Due to restrictions in availability of proper bioactive signals that would selectively stimulate growth of endothelium and immobilization of such signaling molecules on the metal surface, Ceylan et al. had developed self-assembly, pH-dependent, Dopa-conjugated peptide amphiphile and REDV-conjugated peptide amphiphile nanofibers. Those nanofibers had mimicking property of native endothelium extracellular matrix and had been easily immobilized on stainless steel surface. In vitro experiments had showed that peptide nanofiber-coated stainless steel surface had increased adhesion of vascular endothelial cells as against uncoated surface. Besides, it had decreased viability, proliferation of vascular endothelial cells, and platelet attachment to the peptide. It was suggested in this study that this bioactive stent design has provided a futuristic approach for clinical use in prolonged cardiovascular treatments [55].
