Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism

Rutanen, Juha; Am, Turunen; Teittinen, M; Tt, Rissanen; Heikura, Tommi; Jk, Koponen; Gruchała, Marcin; Inkala, Matias; Jauhiainen, Suvi; Mo, Hiltunen; Mp, Turunen; Stacker, Steven A.; Achen, Marc G.; Ylä‐Herttuala, Seppo

doi:10.1038/sj.gt.3302489

Cited by 22 publications

(17 citation statements)

References 38 publications

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“…Normocholesterolemic rabbits were found to benefit from VEGF following an arterial injury; however, since hypercholesterolemia per se appeared to increase plasma VEGF levels in the model, hypercholesterolemic rabbits did not receive any benefit from exogenous VEGF, which may be due to the already increased levels of VEGF and the decreased availability of nitric oxide (7,10). This is consistent with the observations of a previous study that performed adenoviral transfer of VEGF in rabbits, and demonstrated that the therapeutic effect of VEGF was nitric oxide-dependent (11). Two studies using a pig model revealed that liposome-mediated VEGF gene transfer prevented the regression of microvessels, enhanced the accumulation of elastin in the adventitia, reduced the amount of myofibroblasts in the adventitia and induced a healing inflammatory response.…”

Section: Introductionsupporting

confidence: 82%

“…This issue is important since previous studies investigating the use of VEGF for the treatment of restenosis have produced conflicting results (6)(7)(8)(9)(10)(11)(12)(13)(14). In general, the results indicate that when high cholesterol is involved in model establishment, the beneficial effects of VEGF are mitigated (7,12); however, a number of studies using liposome-and virus-mediated VEGF transfer to injured arteries in a variety of animal models have demonstrated similar beneficial results (13,15).…”

Section: Discussionmentioning

confidence: 55%

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Inhibition of intimal hyperplasia via local delivery of vascular endothelial growth factor cDNA nanoparticles in a rabbit model of restenosis induced by abdominal aorta balloon injury

Xie

Yang

Yao

et al. 2015

Experimental and Therapeutic Medicine

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Section: Introductionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 55%

Inhibition of intimal hyperplasia via local delivery of vascular endothelial growth factor cDNA nanoparticles in a rabbit model of restenosis induced by abdominal aorta balloon injury

Xie

Yang

Yao

et al. 2015

Experimental and Therapeutic Medicine

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“…First, systemic adenoviral gene transfer of VEGF-A, -B, -C, or -D, as well as recombinant VEGF-A administration, did not alter plaque area or macrophage influx in LDLR/ApoB48 double knockout mice (36). Second, periadventitial and intra-arterial gene transfer of VEGF-A, -C, and -D has inhibited neointimal growth in many animal studies (37)(38)(39)(40)(41). Third, there has been no evidence of increased atherogenesis in clinical trials using VEGF-A protein or gene transfer (42)(43)(44)(45)(46)(47).…”

Section: Vegf In Blood Vessel Homeostasis and Atherosclerosismentioning

confidence: 98%

Vascular Endothelial Growth Factors

Ylä‐Herttuala

Rissanen

Vajanto

et al. 2007

Journal of the American College of Cardiology

403

129

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Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular biology. They regulate vasculogenesis, angiogenesis, and vascular maintenance during embryogenesis and in adults. Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia. However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization. Here, we review the biology and effects of VEGFs as well as the current status of clinical applications and future perspectives of the therapeutic use of VEGFs in cardiovascular medicine.

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“…The potential of vascular endothelial growth factors (VEGFs), a group of potent endothelial mitogens, to treat postangioplasty restenosis was first investigated in animal models. Several VEGF family members, including VEGF165, VEGF-2, VEGF-C and VEGF-D, have been found to inhibit neointimal thickening, reduce thrombogenicity and restore the endothelium-dependent vasomotor reactivity (27)(28)(29). Yang et al (23) developed a stent coated with bilayered poly-lactide-coglycolide (PLGA) nanoparticles (NPs) containing VEGF plasmid in the outer layer and PTX in the inner core and found that it significantly promotes early endothelium healing while inhibiting SMC proliferation through sequential release of the VEGF gene and PTX (23).…”

Section: Evolution Of Antirestenosis Therapymentioning

confidence: 99%

Gene therapy for in-stent restenosis: Targets and delivery system

Yin¹,

Agrawal²

2014

Curr Res Cardiol

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Despite the increased use of drug-eluting stents (DES), the incidence of in-stent restenosis (ISR) requiring target vessel revascularization remains unacceptably high (1,2). The incidence rate of ISR requiring target vessel revascularization (ie, 'DES failure') in the United States alone was conservatively estimated to be 10%, and may be more common in patients with diabetes mellitus (3). Although the pathophysiology of DES failure is complex, histopathological changes of in-stent neointima following directional atherectomy at the time of reintervention have been shown to be remarkably similar between bare-metal stents (BMS) and DES, suggesting that a process mediated by the endothelial injury, inflammation, proliferation and migration of vascular smooth muscle cells (VSMCs), and thrombosis plays the same important role in the progress of ISR of DES (4,5). In addition, antiproliferative drugs in DES, primarily aimed at preventing VSMC proliferation (which is central to the pathogenesis of ISR), also perturb endothelial recovery (6), which consequently increases the risk for subacute in-stent thrombosis and results in late stent thrombosis (ST) (7). Furthermore, polymer coatings on DES induce a distinct inflammatory reaction compared with bare metal surfaces (8). These results raise serious questions regarding the long-term durability and efficacy of DES, thereby resulting in an urgent need to develop new therapies to prevent restenosis. The present review focuses on the progress made to date in the use of gene therapy, including catheter-based gene delivery and gene-eluting stents (GES), to prevent ISR. We will also discuss the current and promising application of magnetic targeting gene delivery systems for antirestenosis therapy. Evolution of antirEstEnosis thErapyIn the past several decades, percutaneous transluminal coronary angioplasties have revolutionized the treatment of atherosclerosis-related cardiovascular disease. At the same time, tremendous efforts have also been made to reduce the incidence of restenosis after percutaneous transluminal coronary angioplasties (9). During the time in which 'plain old balloon angioplasty' was prevalent, rates of acute and chronic vessel occlusion were higher (30% to 56%), secondary to acute/chronic recoil and constrictive remodelling (10). These problems led to the development of a second revolutionary treatment, BMS, which were first implanted in 1986 (11). Although this 'bailout' scaffold significantly reduced the issue of acute and chronic recoil, its application was ultimately hampered by the risk for subacute thrombotic coronary artery occlusion and neointimal hyperplasia (12). The restenosis rates with BMS were reported to be between 16% and 44%, with higher rates of stenosis attributable to several risk factors, particularly long lesion length and small vessel calibre (1,13). Considerable progress to reduce the incidence of restenosis was made by the advent of DES, which are composed of a metallic stent, a polymer-based drug delivery platform and a pharmacolog...

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Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism

Cited by 22 publications

References 38 publications

Inhibition of intimal hyperplasia via local delivery of vascular endothelial growth factor cDNA nanoparticles in a rabbit model of restenosis induced by abdominal aorta balloon injury

Inhibition of intimal hyperplasia via local delivery of vascular endothelial growth factor cDNA nanoparticles in a rabbit model of restenosis induced by abdominal aorta balloon injury

Vascular Endothelial Growth Factors

Gene therapy for in-stent restenosis: Targets and delivery system

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