Inhibition Of Intimal Hyperplasia Research Articles

Contemporary Use of Drug-Coated Balloons for Coronary Angioplasty: A Comprehensive Review.

The interventional treatment of coronary artery disease (CAD) has undergone significant improvements thanks to technological innovations. Nowadays, percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation is the standard of care for the treatment of CAD. Nevertheless, the non-negligible incidence of in-stent restenosis (ISR) and suboptimal results in various anatomical settings has led to the development of drug-coated balloons (DCBs). DCBs are catheter-based balloons whose surface is coated with an anti-proliferative drug (mainly Paclitaxel or Sirolimus) loaded onto the balloon surface with different technologies and dose concentrations. In the beginning, these devices were used for the treatment of ISR showing an excellent efficacy profile in the inhibition of intimal hyperplasia. Subsequently, several studies evaluated their use in other angiographical and clinical contexts such as de novo lesions, small vessel disease, diffuse coronary disease, bifurcation lesions, acute coronary syndromes, high-bleeding risk and diabetic patients. This comprehensive review aims to describe the main DCB platforms on the market, their fields of application with the main supporting studies and their future perspectives.

Intravascular delivery of an MK2 inhibitory peptide to prevent restenosis after angioplasty

Peripheral artery disease is commonly treated with balloon angioplasty, a procedure involving minimally invasive, transluminal insertion of a catheter to the site of stenosis, where a balloon is inflated to open the blockage, restoring blood flow. However, peripheral angioplasty has a high rate of restenosis, limiting long-term patency. Therefore, angioplasty is sometimes paired with delivery of cytotoxic drugs like paclitaxel to reduce neointimal tissue formation. We pursue intravascular drug delivery strategies that target the underlying cause of restenosis - intimal hyperplasia resulting from stress-induced vascular smooth muscle cell switching from the healthy contractile into a pathological synthetic phenotype. We have established MAPKAP kinase 2 (MK2) as a driver of this phenotype switch and seek to establish convective and contact transfer (coated balloon) methods for MK2 inhibitory peptide delivery to sites of angioplasty. Using a flow loop bioreactor, we showed MK2 inhibition in ex vivo arteries suppresses smooth muscle cell phenotype switching while preserving vessel contractility. A rat carotid artery balloon injury model demonstrated inhibition of intimal hyperplasia following MK2i coated balloon treatment in vivo. These studies establish both convective and drug coated balloon strategies as promising approaches for intravascular delivery of MK2 inhibitory formulations to improve efficacy of balloon angioplasty.

Engineering Immunomodulatory Stents Using Zinc Ion-Lysozyme Nanoparticle Platform for Vascular Remodeling.

Rapid endothelialization of cardiovascular materials can enhance the vascular remodeling performance. In this work, we developed a strategy for amyloid-like protein-assembly-mediated interfacial engineering to functionalize a biomimetic nanoparticle coating (BMC). Various groups (e.g., hydroxyl and carboxyl) on the BMC are responsible for chelating Zn2+ ions at the stent interface, similar to the glutathione peroxidase-like enzymes found in vivo. This design could reproduce the release of therapeutic nitric oxide gas (NO) and an aligned microenvironment nearly identical with that of natural vessels. In a rabbit abdominal aorta model, BMC-coated stents promoted vascular healing through rapid endothelialization and the inhibition of intimal hyperplasia in the placement sites at 4, 12, and 24 weeks. Additionally, better anticoagulant activity and immunomodulation in the BMC stents were also confirmed, and vascular healing was mainly dependent on cell signaling through the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) cascade. Overall, a metal-polypeptide-coated stent was developed on the basis of its detailed molecular mechanism of action in vascular remodeling.

Chitosan inhibits vascular intimal hyperplasia via LINC01615/MIR-185-5p/PIK3R2 signaling pathway

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are the main pathological processes which are involved in the formation of new intima. In our previous study, we found that chitosan can inhibit the formation of new intima in the arteriovenous fistulas of uremic patients, and the expression of LINC01615 was significantly increased in patients after treatment with chitosan. Therefore, this study aims to further explore the effect of chitosan on the intimal hyperplasia and elucidate the potential molecular mechanism. In vitro, we found that in chitosan-treated VSMC, the levels of Il-1β, IL-6 and TNF-α decreased, and the intimal hyperplasia was inhibited along with significantly downregulated PIK3R2 and upregualted PI3K, AKT and p-AKT. Meanwhile, we observed the phenotypic transformation of hVSMCs after LINC01615 was upregulated. In addition, inflammatory factors showed the same changes in the process of up-regulating LINC01615. Moreover, only in the LINC01615 overexpression and miR-185-5p mimic experimental group, the inhibition of intimal hyperplasia was the most obvious. The interaction between LINC01615 and miR-185-5p, miR-185-5p and PIK3R2 was further confirmed by the dual luciferase assay. These results suggest that chitosan has a potential preventive effect on neointimal hyperplasia and related vascular remodeling.

Farrerol Inhibits Vascular Smooth Muscle Cell Proliferation and Protects Them From Oxidative Injury via Bidirectional Modulation of the PI3K/Akt/mTOR Signaling Pathway

The inhibition of intimal hyperplasia (IH) is an effective strategy to improve the long-term outcome of endovascular therapy and prevent restenosis. Farrerol, a naturally occurring dihydroflavone with a variety of bioactivities, exerts inhibitory effects against balloon injury-induced IH in rats. In the present study, bioinformatics analysis, in combination with in vitro experimental validation, was performed to elucidate the underlying inhibitory mechanisms. The protein–protein interaction (PPI) network was assessed to identify farrerol-related protein targets in the context of IH, based on which biological functions and pathway enrichment were analyzed. The proliferation and cell cycle distribution of vascular smooth muscle cells (VSMCs) were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide and 5-ethynyl-2-deoxyuridine incorporation assays and flow cytometric analysis, respectively. The level of pro-inflammatory cytokines in the cell culture medium was estimated using an enzyme-linked immunosorbent assay (ELISA). Protein expression in A7r5 cells was determined by western blotting. Forty-six IH-related targets of farrerol were identified, and the PI3K/Akt/mTOR pathway was highly enriched among the 43 predicted pathways ( P < .05). In serum (10% fetal bovine serum)-induced A7r5 cells, farrerol inhibited proliferation through non-cytotoxic effects, induced cell cycle arrest in the G0/G1 phase , and suppressed the activation of the PI3K/Akt/mTOR pathway. In H2O2 (300 µM)-induced A7r5 cells, farrerol reduced the release of IL-1 β and TNF- α and reversed the suppressive effect on the PI3K/Akt/mTOR pathway in response to H2O2 stimulation. In conclusion, farrerol inhibits the proliferation of VSMCs and protects VSMCs from oxidative injury via the bidirectional modulation of the PI3K/Akt/mTOR signaling pathway, which might contribute to the suppression of neointima formation.

Perivascular application of sirolimus multilayer nanofibrous mat for prevention of vascular stenosis: Preparation, In vitro characterization, and In vivo efficacy evaluation

Graft stenosis, occurring after coronary artery bypass surgery (CABG), diminishes the efficacy and long-term patency of vascular interventions. Multilayer nanofibers (NFs) are developed to provide localized controlled release of sirolimus to prevent vascular stenosis, as well as limit drug exposure to other organs. NFs are composed of a mid-layer of drug and polycaprolactone (PCL), a bioadhesive layer of PCL and collagen, and a backing layer of PCL. NFs are characterized in vitro regarding morphology, mechanical strength, contact angle, water uptake, drug content, and drug release behavior. The average fiber diameter is around 300–500 nm. Sirolimus entrapment is confirmed by drug content, FTIR, and XRD. It is found that sirolimus is released from multilayer NFs in a sustained manner with about half of the payload released over one week. Sirolimus multilayer NFs are implanted in the rat carotid artery after inducing vascular injury. Histological, immunohistochemical (α-SMA, Ki-67, and CD31), and in vivo imaging analyses reveal that the administration of sirolimus multilayer NFs causes significant inhibition of intimal hyperplasia in the rat carotid injury model compared to the control groups and drug suspension. The obtained results reveal that the sirolimus multilayer nanosystem could be a promising carrier for local vascular drug delivery.

Suppression of Cell Proliferation and Macrophage Infiltration with Localized siRNA Delivery in a Murine Model of Intimal Hyperplasia

Intimal hyperplasia limits the durability of peripheral vascular interventions and is associated with cell proliferation and macrophage infiltration. We use an in vivo rat carotid angioplasty model to evaluate inhibition of intimal hyperplasia with localized siRNA delivery targeting Thrombospondin-2 (TSP2) and evaluate its impact on cell proliferation (Ki-67) and macrophage infiltration (CD68). Intimal hyperplasia was induced by Fogarty catheter angioplasty vessel injury of the common carotid artery in 32 rats, which were divided into three control arms and one experimental arm (localized delivery of TSP2-suppressing siRNA). At postoperative day 21, bilateral common carotid arteries were harvested for evaluation of intimal hyperplasia via intima-to-media ratio calculation, PCR quantification of TSP2 mRNA expression, and immunohistochemical staining of Ki-67 proliferative marker and CD68 macrophage marker. RT-PCR data demonstrates successful TSP2 mRNA expression knockdown in the experimental arm compared with the control injury arm (0.49 ± 0.32 vs 20.5 ± 5.47; P = .027). The intima-to-media ratio, a measure of intimal hyperplasia, trended towards a significant decrease in the TSP2 siRNA treatment arm (1.34 ± 0.57 vs 1.94 ± 0.55; P = .056). Reduced macrophage infiltration (CD68 per mm2) was detected in the TSP2 siRNA treatment arm (23 ± 14 vs 72 ± 11; P = .029) as compared with the control injury arm. Furthermore, cell proliferation as measured by Ki-67 per mm2 (Figure) trended towards a significant decrease in the TSP2 siRNA treatment arm (27 ± 19 vs 69 ± 9; P = .067). Localized delivery of TSP2 siRNA can successfully limit the development of intimal hyperplasia in a rat carotid angioplasty model and decrease cell proliferative markers and macrophage infiltration. Further studies in larger animal models are warranted.

Recent strategies for improving hemocompatibility and endothelialization of cardiovascular devices and inhibition of intimal hyperplasia.

Cardiovascular diseases have become one of the leading causes of mortality worldwide. Stents and artificial grafts have been used to treat cardiovascular diseases. Thrombosis and restenosis seriously impact the clinical outcome of stents and artificial vascular grafts. For the purpose of antithrombosis and anti-restenosis, numerous strategies have been developed to construct highly hemocompatible surfaces, enhance endothelialization, and inhibit intimal hyperplasia. Rapid endothelialization and inhibited intimal hyperplasia play an important role in artery repair after stent implantation and coronary artery bypass graft surgery. This review focuses on the recently developed strategies for improving the hemocompatibility and endothelialization of cardiovascular devices. We also introduce drug, gene and RNA delivery technologies for inhibiting intimal hyperplasia. The challenges and future perspectives about promoting endothelialization are also briefly discussed with the hope to help inspire further innovations.

LncRNA H19 abrogates the protective effects of curcumin on rat carotid balloon injury via activating Wnt/β-catenin signaling pathway

Intimal hyperplasia-induced restenosis is a common response to vascular endothelial damage caused by mechanical force or other stimulation, and is closely linked to vascular remodeling. Curcumin, a traditional Chinese medicine, exhibits potent protective effects in cardiovascular diseases; for example, it attenuates vascular remodeling. Although the suppressive effects of curcumin on diseases caused by vascular narrowing have been investigated, the underlying mechanisms remain unknown. Long non-coding RNAs (lncRNAs) regulate various pathological processes and affect the action of drugs. In the present study, we found that the curcumin remarkably downregulated the expression of lncRNA H19 and thereby inhibited intimal hyperplasia-induced vascular restenosis. Furthermore, the inhibition of the expression of H19 by curcumin resulted in the inactivation of the Wnt/β-catenin signaling. Overall, we show that curcumin suppresses intimal hyperplasia via the H19/Wnt/β-catenin pathway, implying that H19 is a critical molecule in the suppression of intimal hyperplasia after balloon injury by curcumin. These insights should be useful for potential application of curcumin as a therapeutic intervention in vascular stenosis.

An adventitial painting modality of local drug delivery to abate intimal hyperplasia

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation. Here we developed a new modality of directly “painting” drug-loaded unimolecular micelles (UM) to the adventitia thus obviating the need for a hydrogel.To render tissue adhesion, we generated amine-reactive unimolecular micelles with N-hydroxysuccinimide ester (UM-NHS) terminal groups to form stable amide bonds with the adventitia. To test periadventitial application, we either soaked balloon-injured rat carotid arteries in crosslinked UM-NHS (Mode-1) or non-crosslinked UM-NHS (Mode-2), or painted the vessel surface with non-crosslinked UM-NHS (Mode-3). The UM-NHS were loaded with or without a model drug (rapamycin) known to be IH inhibitory. We found that Mode-1 produced a marked IH-mitigating drug effect but also caused severe tissue damage. Mode-2 resulted in lower tissue toxicity yet less drug effect on IH. However, the painting method, Mode-3, demonstrated a pronounced therapeutic effect (75% inhibition of IH) without obvious toxicity.In summary, we present a simple painting modality of periadventitial local drug delivery using tissue-adhesive UM. Given the robust IH-abating efficacy and low tissue toxicity, this prototype merits further development towards an effective anti-stenosis therapy suitable for open vascular reconstructions.

Delivery of Thrombospondin-2 Small Interfering RNA for Suppression of Intimal Hyperplasia

Delivery of Thrombospondin-2 Small Interfering RNA for Suppression of Intimal Hyperplasia

Effects of a Matrix Metalloproteinase Inhibitor-Eluting Stent on In-Stent Restenosis.

BackgroundThe aim of this study was to compare changes in the extracellular matrix after implantation of a stent that elutes a matrix metalloproteinase (MMP) inhibitor (GM6001); and to determine the effects of the GM6001-eluting stent upon prevention of in-stent restenosis (ISR).Material/MethodsWe included 48 Guangxi Bama mini-pigs in this study. A GM6001-eluting stent was placed in one iliac artery and a stent that did not elute GM6001 was placed in the contralateral iliac artery. The iliac arteries were removed at 6 hours as well as 1, 7, 14, 56, 84, and 336 days after stent placement. Arteries were analyzed for morphometry, gelatinase content, different phenotypes of vascular smooth muscle cells (VSMCs), collagen content, apoptotic rate, and cell density.ResultsThe vascular lumen areas of the GM6001 group were significantly increased and the neointimal areas were significantly reduced compared with the control group from the 7 days to the 336 days. In the 2 groups, expression of MMP-2 and MMP-9 peaked simultaneously, but GM6001-eluting stents inhibited expression of MMP-2 and MMP-9 in the vascular media and neointima (especially around the struts) significantly. In the GM6001 group, expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2, myosin heavy chain 10 (MYH-10, marker of the proliferative phenotype of VSMCs), collagen content, percentage of apoptotic cells, and cell density were also decreased significantly compared with those in the control group.ConclusionUse of GM6001-eluting stents resulted in persistent and potent inhibition of intimal hyperplasia, an increase in luminal area, and no obvious thrombosis in the arteries of the mini-pigs.

K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms

ObjectiveAbdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models. MethodsA hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model were also used to examine the ability of K-134 to prevent rupture. ResultsK-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol (P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model, K-134 inhibited rupture and significantly improved survival (P < .01). ConclusionsK-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS–Vascular Science 2020;1:219-32.) Clinical RelevanceThis study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA.

Cilostazol as a noninferiority pharmacologic option to paclitaxel in early intimal hyperplasia inhibition after venous balloon angioplasty in a rabbit model: a preliminary study

The development of venous intimal hyperplasia (VIH) has not been fully studied. At present, there are no drugs approved for VIH inhibition; to investigate such alternatives, we aimed to compare paclitaxel with cilostazol in VIH early inhibition in a preliminary experimental model of balloon angioplasty. Twenty-eight male New Zealand rabbits were randomly divided into two groups: cilostazol (A) and paclitaxel (B), which underwent femoral vein barotrauma by a 4 mm balloon angioplasty. The VIH model was previously tested in controls obtaining an 80% increase of subintimal area (SIA) compared with veins without injury (from 0.12 mm2 [standard deviation (SD), 0.05] to 0.86 mm2 [SD, 0.08]). Group A received 20 mg/kg twice daily; group B angioplasty was performed with a single-dose paclitaxel-coated balloon. Seven days later rabbits were euthanized, and vein tissue samples were taken for histological analysis. The primary end point was SIA measure expressed in mm2, and the anticipated difference between treatments was 0.21 mm2. Other measurements were immunohistochemistry expression of hypoxia inducible factor-1 alpha, platelet derived growth factor, and smooth muscle actin, as surrogates of cell migration and oxidative stress. SIA of group A was 0.33 mm2 (SD, 0.15; 95% CI, 0.24-0.42 mm2), and that of group B was 0.31 mm2 (SD, 0.14; 95% CI, 0.22-0.40 mm2). Both drugs showed a reduction of 61% and 63%, respectively, in SIA, compared with controls. The difference between both drugs was 0.0193 mm2 (95% CI, −0.1175 to 0.156 mm2); the statistical difference was found in hypoxia inducible factor-1 alpha expression between both groups. Clinical RelevanceAlthough veins have a thinner middle layer compared with arteries, smooth muscle cells appear to play an important role in venous stenosis after angioplasty. The study of smooth muscle cell response after barotrauma may have clinical applications in the endovascular treatment of venous stenosis, because at the moment, there is no medication indicated to prolong patency after venous endovascular procedures, for example in May Thurner syndrome. Paclitaxel and cilostazol seem to have a promising role. Finally, the present study could inspire a research line to reduce stent placement and increase patency after venous angioplasty.

The placental growth factor attenuates intimal hyperplasia in vein grafts by improving endothelial dysfunction

Saphenous vein grafts (SVG) patency is limited by intimal hyperplasia (IH) caused by endothelial dysfunction. This study aimed to explore the effect of placental growth factor (PlGF) on the endothelial function of SVG. In rat models of external jugular vein-carotid artery graft treated with PlGF or saline hydrogel, PlGF inhibited vein graft IH (day 28: 12.0 ± 1.9 vs. 61.7 ± 13.1 μm, P < 0.001), promoted microvessel proliferation (day 14: 33.3% 3+ vs. 50.0% 2+, P = 0.03), and increased nitric oxide (NO) production (P < 0.05 on days 1/3/5) and NO synthase (NOS) expression by immunohistochemistry. In human umbilical vein endothelial cells (HUVECs) cultured under hypoxia and treated or not with PlGF, PlGF restored the survival (50 ng/ml PlGF, 48 h: 91.7 ± 0.6% vs. 84.9 ± 0.5%, P < 0.01), migration (by Matrigel assay), and tube formation ability (junctions, tubules, and tubule total length; all P < 0.01) of HUVECs after hypoxia. PlGF increased NO production through increased eNOS expression (P < 0.05), without changes in iNOS expression. The mRNA expression of eNOS decreased after the addition of the PI3K inhibitor LY294002 (P < 0.05). PlGF promoted the protein expression of eNOS by up-regulating AKT, and the AKT and eNOS protein levels were decreased after adding LY294002 (all P < 0.05). In conclusion, PlGF is a candidate for the inhibition of IH in SVG after coronary artery bypass graft. The effects of PlGF are mediated by the upregulation of the eNOS mRNA and protein through the PI3K/AKT signaling pathway. PlGF promotes the secretion of NO by endothelial cells and thereby reduces the occurrence and development of IH.

The Cholesteryl Ester Transfer Protein Inhibitor, des-Fluoro-Anacetrapib, Prevents Vein Bypass-induced Neointimal Hyperplasia in New Zealand White Rabbits

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.

Long-term hemodynamic mechanism of enhanced external counterpulsation in the treatment of coronary heart disease: a geometric multiscale simulation.

Enhanced external counterpulsation (EECP) is a noninvasive treatment method for coronary artery atherosclerosis that acts on the vascular endothelial cells. The intracoronary hemodynamic parameters that influence long-term treatment effect are the fundamental factors for the inhibition of intimal hyperplasia, which cannot be measured in real time. In order to optimize the long-term treatment effect of coronary heart disease, it is necessary to establish a method for quantified calculation of intracoronary hemodynamic parameters during counterpulsation to research the long-term hemodynamic mechanism of EECP. A geometric multiscale model coupled by the zero-dimensional (0D) lumped parameter model and the three-dimensional (3D) model of narrow coronary artery was established for the simulation of intracoronary hemodynamic environment. The 3D model was used to calculate the hemodynamic parameters such as wall shear stress (WSS) and oscillatory shear index (OSI), while the 0D model was used to simulate the blood circulatory system. Sequential pressure was applied to calves, thighs, and buttocks module in 0D model with the consideration of vessel collapse. Hemodynamic performance was compared with clinical reports to verify the effectiveness of the method. There were significant increases of the diastolic blood pressure (DBP), coronary flow, and the area-averaged WSS during application of EECP, while OSI behind stenosis has some decrease. The waveforms of coronary flow has good similarity with the clinical measured waveforms, and the differences between calculated mean arterial pressures (MAPs) and clinical measurements were within 1%. The fundamental factor in the cure of coronary heart disease by EECP is the improvement of WSS and the decrease of OSI. Comparing with the clinical reports, the immediate hemodynamic changes demonstrate the effectiveness of model. Intracoronary hemodynamic parameters during EECP could be acquired and the method could be used to simulate the long-term treatment effect of EECP. Graphical abstract.

ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation.

SummaryVascular smooth muscle cell (VSMC) proliferation promotes intimal hyperplasia (IH) in occluding vascular diseases. Here we identified a positive role of ALDH1A3 (an aldehyde dehydrogenase) in this pro-IH process. The expression of ALDH1A3, but not that of 18 other isoforms of the ALDH family, was substantially increased in cytokine-stimulated VSMCs. PDGF(BB) stimulated VSMC total ALDH activity and proliferation, whereas ALDH1A3 silencing abolished this effect. ALDH1A3 silencing also diminished the expression of two matricellular proteins (TNC1 and ESM1), revealing a previously unrecognized ALDH1A3 function. Loss-of-function experiments demonstrated that TNC1 and ESM1 mediated ALDH1A3's pro-proliferative function via activation of AKT/mTOR and/or MEK/ERK pathways. Furthermore, ALDH inhibition with disulfiram blocked VSMC proliferation/migration in vitro and decreased TNC1 and ESM1 and IH in angioplasty-injured rat carotid arteries. Thus, ALDH1A3 promotes VSMC proliferation at least partially through TNC1/ESM1 upregulation; dampening excessive ALDH1A3 activity represents a potential approach to IH mitigation.

Stress and Vascular Responses: Mitogen-Activated Protein Kinases and Activator Protein-1 as Promising Therapeutic Targets of Vascular Remodeling

Mitogen-activated protein kinases (MAP kinases), including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, play a central role in cellular responses by various stress stimuli such as cell proliferation, apoptosis, migration, or gene expression. Furthermore, activator protein-1 (AP-1), a transcription factor which can be activated by MAP kinases, also is involved in a variety of celllar responses, as well as MAP kinases. MAP kinases and AP-1 are significantly activated in vascular tissues by hypertension, angiotensin II, or balloon injury. We have made dominant negative mutants of MAP kinases or c-Jun, to specifically inhibit in vivo activation of MAP kinases or AP-1. Vascular gene transfer of each dominant negative mutant of MAP kinases or c-Jun prevents intimal hyperplasia after balloon injury, which is associated with the inhibition of smooth muscle cell proliferation in the intima and the media and probably also associated with inhibition of smooth muscle cell migration. However, in vitro findings on cultured vascular smooth muscle cells suggest that the molecular mechanism underlying inhibition of intimal hyperplasia may be different among each dominant negative mutant of MAP kinases and c-Jun. MAP kinases and c-Jun seem to be the promising therapeutic target for vascular remodeling.

Copper-Based SURMOFs for Nitric Oxide Generation: Hemocompatibility, Vascular Cell Growth, and Tissue Response.

A coating that can generate nitric oxide (NO) for surface modification of cardiovascular stents with adaptable NO release is an efficient approach to prevent thrombosis and neointimal hyperplasia. Herein, we prepared a copper-based surface-attached metal-organic framework (Cu-SURMOFs) of copper(II) benzene-1,3,5-tricarboxylate (CuBTC) using a layer-by-layer assembly method (LBL) for NO generation on the surface of alkali-activated titanium. It was easy to control surface chemistry and NO release by changing the number of LBL deposition cycles. The obtained CuBTC coating was characterized by X-ray diffraction, scanning electron microscopy, Fourier transform infrared, and X-ray photoelectron spectroscopy analysis and was able to decompose endogenous S-nitrosoglutathoine (GSNO) to catalytically produce NO. The resulting NO flux increased with increased deposition cycles. The coating prepared with 10 cycles of deposition showed ideal NO release and promoted proliferation of endothelial cells, suppressed growth of smooth muscle cells and macrophages, and inhibited platelet adhesion and activation. Further evaluation of thrombogenicity in an arteriovenous shunt model showed that the CuBTC coating had great ability to prevent thrombosis, and in vivo implantation of CuBTC-coated titanium wire demonstrated a significant inhibition of intimal hyperplasia. The results showed that use of copper-based SURMOFs could be a promising strategy for the surface modification of cardiovascular stents.