Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia.

Adenovirus vectors are capable of high efficiency in vivo arterial gene transfer, and are currently in use as therapeutic agents in animal models of vascular disease. However, despite substantial data on the ability of viruses to cause vascular inflammation and proliferation, and the presence in current adenovirus vectors of viral open reading frames that are translated in vivo, no study has examined the effect of adenovirus vectors alone on the arterial phenotype. In a rabbit model of gene transfer into a normal artery, we examined potential vascular cell activation, inflammation, and neointimal proliferation resulting from exposure to replication-defective adenovirus. Exposure of normal arteries to adenovirus vectors resulted in: (a) pronounced infiltration of T cells throughout the artery wall; (b) upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in arterial smooth muscle cells; (c) neointimal hyperplasia. These findings were present both 10 and 30 d after gene transfer, with no evidence of a decline in severity over time. Adenovirus vectors have pleiotropic effects on the arterial wall and cause significant pathology. Interpretation of experimental protocols that use adenovirus vectors to address either biological or therapeutic issues should take these observations into account. These observations should also prompt the design of more inert gene transfer vectors.

[1]  R. Virmani,et al.  Endothelium-specific in vivo gene transfer. , 1995, Circulation research.

[2]  M. Perricaudet,et al.  Low-efficiency of percutaneous adenovirus-mediated arterial gene transfer in the atherosclerotic rabbit. , 1995, The Journal of clinical investigation.

[3]  G. Koretzky,et al.  Adenoviral-mediated gene transfer to fetal pulmonary epithelia in vitro and in vivo. , 1995, The Journal of clinical investigation.

[4]  R. Virmani,et al.  In vivo gene transfer into injured carotid arteries. Optimization and evaluation of acute toxicity. , 1995, Circulation.

[5]  H. Ertl,et al.  Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses , 1995, Journal of virology.

[6]  Y. Kaneda,et al.  Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Wilmott,et al.  Replication-deficient adenovirus induces expression of interleukin-8 by airway epithelial cells in vitro. , 1995, Human gene therapy.

[8]  J. Seltzer,et al.  Cytostatic gene therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product , 1995, Science.

[9]  B. A. French,et al.  Percutaneous transluminal in vivo gene transfer by recombinant adenovirus in normal porcine coronary arteries, atherosclerotic arteries, and two models of coronary restenosis. , 1994, Circulation.

[10]  R. Crystal,et al.  In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Perricaudet,et al.  Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector. , 1994, Circulation.

[12]  E. Nabel,et al.  Gene therapy for vascular smooth muscle cell proliferation after arterial injury. , 1994, Science.

[13]  R. Crystal,et al.  Acute responses of non-human primates to airway delivery of an adenovirus vector containing the human cystic fibrosis transmembrane conductance regulator cDNA. , 1994, Human gene therapy.

[14]  James M. Wilson,et al.  Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis , 1994, Nature Genetics.

[15]  J. Wilson,et al.  Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Furth,et al.  Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Alan E. Smith,et al.  Correction of cAMP-stimulated fluid secretion in cystic fibrosis airway epithelia: efficiency of adenovirus-mediated gene transfer in vitro. , 1994, Human gene therapy.

[18]  J. Wilson,et al.  Adenovirus-mediated gene transfer of soluble vascular cell adhesion molecule to porcine interposition vein grafts. , 1994, Circulation.

[19]  M. Pirwitz,et al.  Genetic modification of the vessel wall. Comparison of surgical and catheter-based techniques for delivery of recombinant adenovirus. , 1994, Circulation.

[20]  R. Ross.  The role of T lymphocytes in inflammation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[21]  T. Eberlein,et al.  T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[22]  E. Nabel,et al.  Complex models for the study of gene function in cardiovascular biology. , 1994, Annual review of physiology.

[23]  R. Virmani,et al.  Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall. Modeling with microscopic tracer particles and verification with a recombinant adenoviral vector. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[24]  P. Libby,et al.  Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma. , 1993, The American journal of pathology.

[25]  R. Crystal,et al.  Efficient and Selective Adenovirus‐Mediated Gene Transfer Into Vascular Neointima , 1993, Circulation.

[26]  J. Wilson,et al.  Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. , 1993, Human gene therapy.

[27]  R. Virmani,et al.  In vivo adenoviral vector-mediated gene transfer into balloon-injured rat carotid arteries. , 1993, Circulation research.

[28]  B. A. French,et al.  The Advent of Adenovirus Gene Therapy for Cardiovascular Disease , 1993, Circulation.

[29]  P. Libby,et al.  Sustained Activation of Vascular Cells and Leukocytes in the Rabbit Aorta After Balloon Injury , 1993, Circulation.

[30]  B. Davidson,et al.  Adenoviral-mediated gene transfer to rabbit synovium in vivo. , 1993, The Journal of clinical investigation.

[31]  P. Libby,et al.  Vascular cell adhesion molecule-1 and smooth muscle cell activation during atherogenesis. , 1993, The Journal of clinical investigation.

[32]  M. Ferguson,et al.  Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. , 1993, The Journal of clinical investigation.

[33]  J. Wilson,et al.  Gene therapy: adenovirus vectors. , 1993, Current opinion in genetics & development.

[34]  R. Crystal,et al.  In vivo gene transfer and expression in normal uninjured blood vessels using replication-deficient recombinant adenovirus vectors. , 1993, Circulation research.

[35]  R. Crystal,et al.  Adenovirus-mediated augmentation of cell transfection with unmodified plasmid vectors. , 1993, The Journal of biological chemistry.

[36]  P. Libby,et al.  An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[37]  M P Bevilacqua,et al.  Endothelial-leukocyte adhesion molecules. , 1993, Annual review of immunology.

[38]  J. Vierling,et al.  Up-regulation of intercellular adhesion molecule 1 transcription by hepatitis B virus X protein. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Gown,et al.  Various cell types in human atherosclerotic lesions express ICAM-1. Further immunocytochemical and immunochemical studies employing monoclonal antibody 10F3. , 1992, The American journal of pathology.

[40]  J. Coucher,et al.  Expression of intercellular adhesion molecule-1 in atherosclerotic plaques. , 1992, The American journal of pathology.

[41]  D. Hajjar.  Warner-Lambert/Parke-Davis Award Lecture. Viral pathogenesis of atherosclerosis. Impact of molecular mimicry and viral genes. , 1991, The American journal of pathology.

[42]  R. Silverstein,et al.  Identification of a monocyte receptor on herpesvirus-infected endothelial cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Cybulsky,et al.  Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. , 1991, Science.

[44]  F. Graham,et al.  Manipulation of adenovirus vectors. , 1991, Methods in molecular biology.

[45]  A. Gown,et al.  A smooth muscle-specific monoclonal antibody recognizes smooth muscle actin isozymes , 1985, The Journal of cell biology.

[46]  Ph.D. David R. Gross D.V.M..  Animal Models in Cardiovascular Research , 1985, Springer Netherlands.

[47]  T. Kindt,et al.  Differentiation antigens identify subpopulations of rabbit T and B lymphocytes. Definition by flow cytometry , 1983, The Journal of experimental medicine.

[48]  H. B. Mann,et al.  On a Test of Whether one of Two Random Variables is Stochastically Larger than the Other , 1947 .