Reduction in Vascular Lesion Formation by Hirudin Secreted From Retrovirus-Transduced Confluent Endothelial Cells on Vascular Grafts in Baboons

Lundell, Anders; Kelly, Andrew B.; Anderson, Johanna S.; Marijianowski, Monique M.H.; Rade, Jeffrey J.; Hanson, Stephen R.; Harker, Laurence A.

doi:10.1161/01.cir.100.19.2018

Cited by 8 publications

(3 citation statements)

References 40 publications

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“…Adenovirus vectors have been used to successfully transfect over 90% of cultured endothelial cells (7, 8). Adenovirus vectors have also been tested as in vivo for possible application in gene therapy (7, 17). The use of viral transfection vectors, though effective, is labor intensive and expensive, and requires dedicated facilities.…”

Section: Discussionmentioning

confidence: 99%

High‐efficiency transient transfection of endothelial cells for functional analysis

et al. 2000

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The definition of signaling pathways in endothelial cells has been hampered by the difficulty of transiently transfecting these cells with high efficiency. This investigation was undertaken to develop an efficient technique for the transfection of endothelial cells for functional analyses. Cells cotransfected with plasmid expressing green fluorescent protein (GFP) and the plasmid of interest were isolated by fluorescence-activated cell sorting (FACS) based on GFP expression. In the sorted cell population, a 2.5-fold enhancement in the number of cells expressing the gene of interest was observed, as confirmed by FACS analysis and Western blotting. Sorted cells retained functional properties, as demonstrated by chemotaxis to the agonist sphingosine 1-phosphate (SPP). To demonstrate the usefulness of this method for defining cellular signaling pathways, cells were cotransfected with plasmids encoding GFP and the carboxyl-terminal domain of the beta-adrenergic receptor kinase (beta ARKct), which inhibits signaling through the beta gamma dimer of heterotrimeric G-proteins. SPP-induced chemotaxis in sorted cells coexpressing beta ARKct was inhibited by 80%, demonstrating that chemotaxis was driven by a beta gamma-dependent pathway. However, no significant inhibition was observed in cells transfected with betaARKct but not enriched by sorting. Thus, we have developed a method for enriching transfected cells that allows the elucidation of crucial mechanisms of endothelial cell activation and function. This method should find wide applicability in studies designed to define pathways responsible for regulation of motility and other functions in these dynamic cells.

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Section: Discussionmentioning

confidence: 99%

High‐efficiency transient transfection of endothelial cells for functional analysis

et al. 2000

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“…Baboons have been used to study effects of hemodynamics and antithrombotic therapy on neointima development in AVGs (27,28) and to evaluate bioengineered grafts (29). However, baboon purchase and care is expensive, and there is significant public opposition to the use of nonhuman primates in research.…”

Section: Animal Models Of Av Accessmentioning

confidence: 99%

Novel Therapies for Hemodialysis Vascular Access Dysfunction

Terry

Dember

2013

Clinical Journal of the American Society of Nephrology

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SummaryHemodialysis vascular access dysfunction is a major source of morbidity for patients with ESRD. Development of effective approaches to prevent and treat vascular access failure requires an understanding of the underlying mechanisms, suitable models for preclinical testing, systems for targeted delivery of interventions to maximize efficacy and minimize toxicity, and rigorous clinical trials that use appropriate outcome measures. This article reviews the substantial progress and ongoing challenges in developing novel treatments for arteriovenous vascular access failure and focuses on localized rather than systemic interventions.

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“…Further support for the hypothesis that thrombin mediates the formation of neointimal vascular lesions comes from studies performed in baboons. In this study, hirudin was delivered using retrovirus-transduced hirudin-secreting vascular endothelial cells (ECs) that were surgically implanted via arterial vascular grafts (AVGs) (39). Hirudin is a thrombin inhibitor that binds irreversibly to thrombin at multiple sites.…”

Section: Thrombosismentioning

confidence: 99%

Gene Transfer Therapy in Vascular Diseases

McKay

Gaballa

2001

Cardiovascular Drug Reviews

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Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo. Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations. The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of angiogenesis in the cardiac muscle are discussed in reviews by several investigators (13,26,57, 74,83). In another review, Meyerson et al. (43) discuss advances in gene therapy for vascular proliferative disorders and chronic peripheral and cardiac ischemia.

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Reduction in Vascular Lesion Formation by Hirudin Secreted From Retrovirus-Transduced Confluent Endothelial Cells on Vascular Grafts in Baboons

Abstract: Viral vector-directed secretion of hirudin from ECs lining implanted AVGs significantly reduces the formation of thrombus and neointimal vascular lesions.

Cited by 8 publications

References 40 publications

High‐efficiency transient transfection of endothelial cells for functional analysis

High‐efficiency transient transfection of endothelial cells for functional analysis

Novel Therapies for Hemodialysis Vascular Access Dysfunction

Gene Transfer Therapy in Vascular Diseases

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