Extent Of Neointima Formation Research Articles

MFG-E8 Regulates Vascular Smooth Muscle Cell Migration Through Dose-Dependent Mediation of Actin Polymerization.

BackgroundMigration of vascular smooth muscle cells (VSMCs) is the main contributor to neointimal formation. The Arp2/3 (actin‐related proteins 2 and 3) complex activates actin polymerization and is involved in lamellipodia formation during VSMC migration. Milk fat globule‐epidermal growth factor 8 (MFG‐E8) is a glycoprotein expressed in VSMCs. We hypothesized that MFG‐E8 regulates VSMC migration through modulation of Arp2/3‐mediated actin polymerization.Methods and ResultsTo determine whether MFG‐E8 is essential for VSMC migration, a model of neointimal hyperplasia was induced in the common carotid artery of wild‐type and MFG‐E8 knockout mice, and the extent of neointimal formation was evaluated. Genetic deletion of MFG‐E8 in mice attenuated injury‐induced neointimal hyperplasia. Cultured VSMCs deficient in MFG‐E8 exhibited decreased cell migration. Immunofluorescence and immunoblotting revealed decreased Arp2 but not Arp3 expression in the common carotid arteries and VSMCs deficient in MFG‐E8. Exogenous administration of recombinant MFG‐E8 biphasically and dose‐dependently regulated the cultured VSMCs. At a low concentration, MFG‐E8 upregulated Arp2 expression. By contrast, MFG‐E8 at a high concentration reduced the Arp2 level and significantly attenuated actin assembly. Arp2 upregulation mediated by low‐dose MFG‐E8 was abolished by treating cultured VSMCs with β1 integrin function‐blocking antibody and Rac1 inhibitors. Moreover, treatment of the artery with a high dose of recombinant MFG‐E8 diminished injury‐induced neointimal hyperplasia and reduced VSMC migration.ConclusionsMFG‐E8 plays a critical role in VSMC migration through dose‐dependent regulation of Arp2‐mediated actin polymerization. These findings suggest that high doses of MFG‐E8 may have therapeutic potential for treating vascular occlusive diseases.

The Canonical Wnt Pathway in the Pathogenesis of Cardiac Allograft Vasculopathy

The canonical wnt pathway with its central signaling molecule β-catenin is important for tissue development and homeostasis and its dysregulation leads to many diseases including pathologies of the cardiovascular system. Inhibition of the wnt pathway has the potential to protect against cardiac allograft vasculopathy (CAV), because it reduces the proliferation of smooth muscle cells (SMCs), which is a main pathomechanism of CAV and causes neointima formation and vessel occlusion. For in vitro experiments human (hu) and murine (mu) aortic SMCs were grown in the presence of increasing concentrations of wnt inhibitors, such as XAV-939, ICG-001 or PKF118-310. Cell proliferation was measured as the extent of PrestoBlue Cell Viability Reagent metabolism and expression of representative wnt target genes was assessed by Taqman PCR. Additionally, the wnt inhibitors were used in the mouse model of aortic transplantation (n=8 mice/group) and the extent of neointima formation as an indicator for CAV was analyzed. We also measured the expression of β-catenin (immunofluorescence staining), wnt target genes (Taqman PCR) and several inflammatory cytokines (Taqman PCR) in the transplant. In vitro experiments revealed dose-dependent proliferation inhibition in huSMCs and muSMCs after treatment with each wnt inhibitor. PKF118-310 induced cell death in the highest concentrations tested. While XAV-939 had only minor influence on the expression of the wnt target genes cyclin D1, axin2 and p21, ICG-001 and PKF118-310 induced the expression of p21 and cyclin D1 and reduced the expression of axin2. Interestingly, in vivo experiments showed no effect of XAV-939 and ICG-001 on neointima formation, whereas neointimal amounts of β-catenin were significantly reduced. ICG-001 also reduced the expression of inflammatory cytokines (INFγ, TNFα and IL-6) and of p21, but did not influence cyclin D1 expression. XAV-939 had no relevant influence on cytokine expression. Results for PKF118-310 and wnt target gene expression in transplants after XAV-939 treatment are currently assessed. Strong anti-proliferative effects were found in vitro for all three wnt inhibitors, but this did not lead to reduced CAV development in a mouse model of vessel transplantation. Effects on SMCs themselves after ICG-001 and PKF118-310 seem indeed mediated via regulation of wnt target genes.

A prospective, multicenter, randomized OCT study of early neointimal condition at first and second months after BuMA Supreme stent versus XIENCE stent implantation in high-bleeding-risk coronary artery disease patients: study protocol for a randomized controlled trial

BackgroundEarlier vascular healing after drug-eluting stent (DES) implantation may reduce the incidence of late stent thrombosis and provide theoretical evidence to shorten dual antiplatelet therapy duration in patients with high bleeding risks. The BuMA supreme stent is a newly developed DES-coated with the sirolimus by using the international patent electronic grafted eG™ technology. Previous randomized trials showed that BuMA stents had better stent-strut coverage at 3-month follow-ups, which were evaluated by optical coherence tomography (OCT). However, there have been a limited number of studies that are directly evaluating the extent of neointima formation at the first and second months after stent implantation in high-bleeding-risk patients with coronary artery disease. This clinical trial is designed to demonstrate the non-inferiority of the BuMA supreme stent compared to the XIENCE stent in early neointimal formation.Methods/designThis is a prospective, multicenter, randomized trial. Forty patients will be assigned into the first-month OCT group, and another 40 patients into the second-month OCT group. The patients in each cohort will be randomized again into two groups in a 1:1 ratio, either being implanted with the BuMA Supreme stent or the Xience V/Prime/Xpedition stent. The primary endpoint is stent-strut neointimal coverage rate (%) at the first and second months, respectively. Secondary endpoints include neointimal hyperplasia area/volume, neointimal hyperplasia thickness, stent-strut malapposition rate, late lumen loss (LLL), restenosis rate, device/lesion/clinical success rate, device-oriented composite endpoints at the first and second months, stent thrombosis and other serious adverse events and bleeding events at follow-up.DiscussionThe results will provide the first accurate imaging evidence on neointimal formation of the BuMA Supreme stent and the Xience stent at 1–2 months post PCI. The result should inspire further exploration and adjustment of DAPT treatments.Trial registrationClinicalTrials.gov, ID: NCT02747329. Registered on 21 April 2016. Last updated 17 May 2018.

TCT-574 First Randomized Evaluation of the Extent of Neointimal Formation between Two Types of Sirolimus-Eluting Stents with Different Designs on Biodegradable Polymer Coatings: The BuMA-OCT Trial

TCT-574 First Randomized Evaluation of the Extent of Neointimal Formation between Two Types of Sirolimus-Eluting Stents with Different Designs on Biodegradable Polymer Coatings: The BuMA-OCT Trial

Role of class IA PI 3-kinase isoforms in neointima formation following balloon angioplasty: only p110alpha is important

Growth factor induced proliferation and migration of vascular smooth muscle cells (SMCs) are essential for neointima formation following balloon angioplasty. Growth factors such as platelet-derived growth factor (PDGF) activate receptor tyrosine kinases (RTKs). RTK-induced responses are largely mediated by activation of class IA phosphatidylinositol 3'-kinase (PI3K) isoforms. Class IA PI3Ks comprise one of three different catalytic isoforms (p110alpha, p110beta, p110delta). Here, we sought to clarify, which p110 subunits contribute to neointima formation following balloon injury. Western blot analysis of lysates from cultured human, mouse and rat SMCs revealed that p110alpha, p110beta, and p110delta are expressed in these cells. However, co-immunoprecipitation experiments using an antibody against the PDGF beta receptor indicate that only p110alpha and p110delta bind to activated RTKs. p110beta signals downstream of G-protein coupled receptors (GPCR) as p110beta inhibition by TGX-221 (1μM) completely abrogated LPA (GPCR agonist) induced AKT activation downstream of PI3K. TGX-221 had no influence on RTK induced AKT activation. Inhibition (PIK75, 500 nM) or siRNA mediated knockdown of p110alpha completely abrogated PDGF mediated proliferation (BrdU incorporation assay) and migration (modified Boyden-chamber) of SMCs. p110beta (TGX-221, 3μM) and p110delta (IC87114, 3μM) inhibition had no influence. However, knockdown of p110delta using a specific siRNA significantly reduced PDGF induced SMC proliferation without effecting SMC migration. As expected, siRNA against p110beta was noneffective. By means of SMC-specific p110alpha deficient mice and p110delta knockout mice, we analysed in vivo the relevance of p110alpha and p110delta for restenosis formation following balloon angioplasty. The extent of neointima formation was quantified 4 weeks following balloon angioplasty of carotid arteries from wild-type (WT) and p110alpha ko as well as from WT and p110delta ko mice (n=7, respectively). Whereas p110alpha deficiency largely suppressed neointima formation (p<0.05), p110delta deficiency was noneffective. In conclusion, our results indicate that the p110alpha subunit of PI3K, is crucial for growth factor-mediated proliferation and migration of SMCs in restonosis following balloon angioplasty. Therefore, p110alpha represents a promising therapeutic target.

OCT-Verified Peri-Strut Low-Intensity Areas and the Extent of Neointimal Formation After 3 Years Following Stent Implantation

Drug eluting stents (DES) have decreased substantially the neointimal formation after percutaneous coronary intervention (PCI). However, DES are not free from neointimal hyperplasia (NIH) and stent thrombosis, which are related to the delayed arterial healing following DES implantation. The recently

Vascular response to intra-arterial injury in the thrombospondin-1 null mouse

Thrombospondin-1 (TSP-1) is a multifunctional, extracellular matrix protein that has been implicated in the regulation of smooth muscle cell proliferation, migration and differentiation during vascular development and injury. Vascular injury in wildtype and TSP-1 null mice was carried out by insertion of a straight spring guidewire into the femoral artery via a muscular arterial branch. Blood flow was restored after the muscular branch was ligated. The injury completely denuded the endothelium and caused medial distension of the vessel in a manner similar to coronary artery balloon-angioplasty. After 28 days, wildtype arteries showed consistent neointima formation with smooth muscle cell hyperplasia. Injured arteries from TSP-1 null mice showed similar neointimal lesions with no significant difference in the extent of neointima formation. Unexpectedly, a high incidence of thrombus formation was observed in the TSP-1 null vessels in a region close to the entry point of the guidewire into the femoral artery. Thrombus was never observed in the injured wildtype vessels. These results provide in vivo evidence that the extent of smooth muscle cell proliferation and neointima formation following endothelial denuding injury is not affected by the absence of TSP-1. Furthermore, our results provide novel evidence for the involvement of TSP-1 in controlling thrombus growth following intra-arterial injury in areas of predicted high turbulent flow.

Comparative study of tacrolimus and paclitaxel stent coating in the porcine coronary model

Tacrolimus is a potent antiproliferative and immunosuppressive agent allowing for improved endothelial regeneration. The aim of our study was the preclinical evaluation of tacrolimus in a drug eluting nonerodable polymer stent system and its comparison with paclitaxel. A total of 40 domestic pigs and 10 mini-pigs underwent coronary stenting with a follow-up time between 6 hours and 3 months. Stents were implanted in coronary arteries with an overstretch ratio of 1.2. After 3 days, a 1.73 microg/mm(2) coating produced tacrolimus tissue levels of 20 mumol/l in the coronary artery wall. Effective tissue concentrations were sustained for 28 days. Based on histomorphometric analysis, tacrolimus stent treated vessels had a reduced extent of neointima formation compared with controls at 28 days (-51% compared to control) but not at 3 months. High dose paclitaxel stent coating (1.44 microg/mm(2)) was complicated by unexpected deaths of pigs and thrombotic stent occlusion at control angiography. Long-term porcine data showed no persistent inhibition of neointimal growth by paclitaxel and tacrolimus stent coating. Similar to paclitaxel, tacrolimus stent coating reduces neointimal proliferation in the porcine coronary model. However, dosing and long-term efficacy remains a critical issue in stent-based local drug delivery.

A porcine coronary stent model of increased neointima formation in the left anterior descending coronary artery.

Clinical trials suggest an increased frequency of restenosis after coronary intervention in left anterior descending (LAD) compared to the left circumflex or right coronary arteries. Experimental studies correlate stent-induced arterial injury and the extent of neointima formation. This study investigates whether the coronary artery affects the relationship between arterial injury and neointima hyperplasia in the porcine stent model. Non-lipemic farm pigs underwent stent placement in the LAD (n = 26) and the right coronary artery (RCA; n = 30). Quantitative coronary angiography (QCA) was performed before and after stent placement, and at follow-up; quantitative histomorphometry and injury score were analyzed at 30-day follow-up. Initial procedure balloon/artery ratios (LAD 1.17 +/- 0.11 vs RCA 1.17 +/- 0.09, P = NS), and minimal stent lumen diameters (MLD; LAD 2.91 +/- 0.31 vs RCA: 2.93 +/- 0.28 mm, P = NS) were similar suggesting no difference in deployment technique. At follow-up there was more restenosis in the LAD (diameter stenosis: 55.0 +/- 26.4% vs 37.3 +/- 18.1%, and MLD: 1.24 +/- 0.78 mm vs. 1.71 +/- 0.57 mm, P < 0.05 for both comparisons). No differences were seen for injury score (1.09 +/- 0.51 vs 1.01 +/- 0.57; LAD vs RCA) or stent area (6.13 +/- 0.99 vs 6.55 +/- 1.42 mm2). Histomorphometry demonstrated smaller lumen area (2.15 +/- 0.94 vs 2.96 +/- 1.29 mm2) and thicker neointima (0.63 +/- 0.25 vs 0.51 +/- 0.17 mm; all P < 0.05) in the LAD. Multiple linear regression analysis identified the LAD as an independent predictive factor for increased neointima formation. These observations establish an animal model that is consistent with clinical experience showing that restenosis after stenting is more common in the LAD. The findings may be useful for understanding and developing systemic and local antirestenotic strategies.

Neointima Formation in the Rat Carotid Artery is Exacerbated by Dietary Copper Deficiency

Dietary copper is an essential trace element with roles in both functional and structural aspects of the cardiovascular system. In particular, the vascular response to inflammatory stimuli is known to be significantly augmented in copper-deficient rats. The current study was designed to quantify the extent of injury-induced neointimal proliferation and stenosis in rats fed diets either adequate or deficient in copper. Male, weanling Sprague-Dawley rats were fed purified diets that were either adequate (CuA; 5.6 microg Cu/g) or deficient (CuD; 0.3 microg Cu/g) in copper for 4 weeks. Balloon injury was induced in the left external carotid arteries. Fourteen days after injury, histomorphometric analysis of cross-sections from carotid arteries showed increased neointimal formation in the CuD group compared with the CuA controls (neointima/media ratio: 4.55 +/- 0.93 vs 1.45 +/- 0.2, respectively). These results correspond with data indicating that the activity of Cu/Zn-superoxide dismutase (SOD) is depressed in rats fed this CuD diet. Because superoxide anion and redox status are known to play a key role in the extent of neointimal formation in response to injury, we propose that the exaggerated neointimal proliferation seen in the CuD group is the result of the diminished Cu/Zn-SOD activity.

Steroid receptor coactivator-3 is required for inhibition of neointima formation by estrogen.

The vasoprotective effects of estrogen are mediated by estrogen receptors (ERs). ERs are transcription factors that require coactivators to exert transcriptional activity. The steroid receptor coactivator-3 (SRC-3, also known as pCIP, AIB1, ACTR, and TRAM-1) interacts with estrogen-bound ERs and strongly coactivates the transcription of target genes in cultured cells. This study has characterized the expression of SRC-3 in cardiovascular tissue and the role of SRC-3 in estrogen-dependent vasoprotection from vascular injury. Phenotypically normal SRC-3(+/-) mice with a knock-in LacZ reporter were used to characterize SRC-3 expression by X-gal staining within the cardiovascular system. Staining signals were specifically detected in vascular smooth muscle cells and endothelial cells but not in myocardial cells. The role of SRC-3 during vascular remodeling was analyzed using a unilateral carotid ligation model. The extent of neointima formation in SRC-3(-/-) mice was significantly higher than in wild-type mice, and this difference was diminished after depletion of estrogen by ovariectomy. After ovariectomy, neointimal growth in wild-type mice was almost completely inhibited by estrogen treatment but only partially inhibited in SRC-3(-/-) mice. Furthermore, estrogen treatment resulted in reduced inhibition of intimal cell proliferation in SRC-3(-/-) mice. SRC-3 is highly expressed in vascular smooth muscle cells and endothelial cells. The loss of SRC-3 function causes a decrease in sensitivity of estrogen-mediated inhibition of neointimal growth, which may be attributable to an insufficient suppression of vascular cell proliferation. These results indicate that SRC-3 largely facilitates ER-dependent vasoprotective effects under conditions of vascular trauma.

Metallische Biowerkstoffe für koronare Stents

The introduction of coronary stents is a milestone in interventional cardiology. Two landmark studies have shown that stainless steel stents significantly decrease the restenosis rate as compared to balloon angioplasty. This fact led to a marked increase of stent implantation since the first stent implantation by Jacques Puel in 1986. Although the concept of coronary stenting significantly improved the interventional therapy of coronary artery disease, restenosis remains a major unsolved drawback of this technique. In addition to procedure and disease related factors like implantation pressure and plaque burden, data suggest that the stent as a medical implant plays a crucial role in the process of neointima formation. Since its introduction in cardiology, more than 50 different stents of different configuration and material have been developed. Although recent publications report of promising results using biodegradable materials, almost all coronary stents commercially available at the moment are made of metallic alloys. Whereas first generation stents were made exclusively from stainless steel and only minor interest was focussed on the stent material in the manufacture of coronary stents, recent studies strongly suggest that the metallic alloy used has a direct impact on the extent of neointima formation. Thus, metallic alloys differ not only with respect to mechanical features, but also by their biocompatible properties. These two factors are of major importance in the induction of vessel wall injury, inflammatory processes and cell proliferation. In the first part, the present paper reviews the metallurgic characteristics of metallic materials, which are currently used or under investigation in the production of coronary stents. In the second part, clinical and experimental results are summarized with respect to their biocompatibility and impact on the process of restenosis formation.

Specific cellular features of atheroma associated with development of neointima after carotid endarterectomy: the carotid atherosclerosis and restenosis study.

The purpose of this study was to investigate whether some cellular and molecular features of tissue retrieved at carotid endarterectomy are associated with the extent of neointima formation at ultrasound follow-up. One hundred fifty patients were studied. Endarterectomy specimens were tested by immunocytochemistry with the use of (1) monoclonal antibodies that identify smooth muscle cells (SMCs) and fetal-type SMCs on the basis of smooth muscle and nonmuscle myosin content, (2) the anti-macrophage HAM 56, and (3) the anti-lymphocyte CD45RO. The maximum intima-media thickness (M-IMT) of the revascularized vessel was assessed by the use of B-mode ultrasonography 6 months after surgery. The M-IMT values were related positively to the number of SMCs (r=0.534, P<0.0005) and negatively to that of macrophages and lymphocytes (r=-0.428, P<0.0005, and -0.538, P=0.001, respectively). Patients were classified as class 1 (M-IMT </=1.0 mm), class 2 (1. 0<M-IMT</=1.3 mm), and class 3 (M-IMT >1.3 mm). An abundance of SMCs, mostly of fetal type, was found in the plaque of class 3 patients, whereas lesions from class 1 patients were rich in macrophages and lymphocytes. In the multivariate analysis, factors related to M-IMT were the number of SMCs and the percentage of fetal-type SMCs present in the plaque. Although the classic risk factors did not play a role, an abundance of SMCs and a scarcity of macrophages characterized the primary lesion of patients in whom neointima developed after surgery. In patients in whom neointima did not develop, lesions were rich in macrophages and lymphocytes. This approach can be useful in defining patients at risk of restenosis.

Experimental evaluation of a short transitional edge protection balloon for intracoronary stent deployment.

The purpose of this study was to determine if balloon injury to the adjacent arterial wall during intracoronary stent deployment influences late in-stent neointimal formation. Stent design and deployment techniques are considered important factors in determining acute and long-term success with intracoronary stenting. Experimental and clinical studies support that the extent of neointimal formation and the probability for restenosis are influenced by the magnitude of arterial trauma induced with stenting. Nineteen 18-mm-long balloon-expandable stainless steel stents (MULTI-LINK Duet) were implanted at a 1:1 stent-to-artery ratio in the coronary arteries of swine with a conventional noncompliant balloon (n = 10) or a novel noncompliant balloon with short tapered shoulders to prevent edge dissection (n = 9). Quantitative coronary angiography and histology were used to evaluate balloon and artery interactions and the chronic vascular responses to the stents. Nineteen stents were implanted in the coronary arteries of seven swines at an inflation pressure of 14 atm using a standard noncompliant (n = 10) or a unique short transitional edge protection (n = 9) balloon. Histologic analysis at 28 days demonstrated balloon-associated barotrauma in 13 of 20 (65%) of adjacent nonstented arterial segments with the conventional balloon and only 3 of 18 (17%) of the adjacent nonstented arterial segments with the short transition edge protection balloon (P = 0.022). In-stent neointimal area and % stenosis correlated with the severity of peristent arterial injury (r = 0.43, P = 0.01). In-stent vessel injury scores were similar for stents with peristent injury (1.0+/-0.3) versus stents without peristent injury (1.0+/-0.03, P = 0.73). In-stent neointimal area and % stenosis were greater for stents with peristent injury (2.36+/-0.74 mm(2), 32%+/-9%) as compared to stents without peristent injury (1.39+/-0.70 mm(2), 20%+/-10%, P = 0.01). Arterial wall injury adjacent to a stent after high-pressure deployment contributes to late in-stent neointimal hyperplasia in this model. These experimental data suggest that further study is warranted to refine stent implantation techniques and that modifications of balloon shape or material may be useful to optimize stent deployment and reduce arterial trauma.

Arterial Injury Increases Expression of Inflammatory Adhesion Molecules in the Carotid Arteries of Apolipoprotein-E-Deficient Mice1

Recent studies demonstrate increased cellular adhesion molecule expression by neointimal endothelium overlying primary and restenotic atherosclerotic plaque. In this study, we developed an atherosclerotic mouse model of arterial injury and characterized adhesion molecule expression after injury. Sixteen apolipoprotein-E-(ApoE)-deficient mice fed a Western-type diet for 4 weeks underwent carotid artery wire denudation at week 2. For each segment, the extent of neointima formation and medial thickening, or adhesion molecule expression, were scored separately on a scale from 0 (no plaque/thickening or expression) to 3 (extensive plaque/thickening or expression) using Movat staining (n = 3) or immunohistochemical analysis (n = 13). Histology revealed significant medial thickening (1.8 ± 0.9 vs. 0.3 ± 0.5, p < 0.001) versus controls and pronounced staining for monocytes/macrophages in the wall of injured vessels. Immunohistochemical analysis showed more robust expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the luminal surface of injured arteries versus controls (2.2 ± 0.6 vs. 1.4 ± 0.7, p < 0.01, and 2.5 ± 0.5 vs. 1.2 ± 0.6, p < 0.001, respectively). Injury increased adventitial ICAM-1 expression (2.6 ± 0.5 vs. 1.6 ± 0.5, p < 0.002) and medial VCAM-1 expression (2.2 ± 0.6 vs. 1.2 ± 0.7, p < 0.004). Thus, carotid injury results in significant medial thickening and increases adhesion molecule expression beyond that induced in ApoE-deficient mice fed a Western diet alone. The observation of macrophage infiltration into the media at sites of increased ICAM-1 and VCAM-1 expression suggests that these molecules may mediate monocyte/macrophage trafficking into the wall of injured arteries.

Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation.

Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.

Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo.

This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo. Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site. A poly-L-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n=6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination. Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47+/-5% vs. 25+/-4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05). These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.