RESUMO
The objective of this work was to develop a platform to evaluate and deliver putative therapeutic agents for in-stent restenosis. Arterial stenting is applied in more than 60% of balloon angioplasties for treating cardiovascular disease. However, stented arteries encounter accelerated rates of restenosis. No prior platform has allowed evaluation or local management of in-stent restenosis without perturbing the very system being examined. A stainless steel, balloon-expandable stent was modified to serve as an ablumenal drug delivery platform. Several combinations of bioerodible polymer microspheres and gels were evaluated for channel retention under in vitro flow and in vivo conditions. A stent-anchored hybrid system prevented material embolization under all conditions. Unlike prior platforms, these stents do not alter local inflammation or in-stent plaque formation relative to conventional Palmaz-Schatz stents after in vivo deployment. The system also proved sensitive enough to detect plaque reduction with an antirestenotic agent. We conclude that a platform to evaluate and deliver therapeutic agents for in-stent restenosis has been achieved.
Assuntos
Reestenose Coronária/prevenção & controle , Stents , Animais , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Sistemas de Liberação de Medicamentos , Desenho de Equipamento , Géis , Humanos , Inflamação/etiologia , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Microesferas , Coelhos , Stents/efeitos adversos , Engenharia TecidualRESUMO
PURPOSE: Alpha-1-antitrypsin (AAT) is the major circulating elastase inhibitor. Deficiency of elastase inhibition leads to emphysema and vascular abnormalities including accelerated neointima. Because recent evidence suggests that tissue AAT levels determine inhibitory function, the authors hypothesize that local tissue-based expression of AAT limits elastase activity sufficiently to guide arterial response to injury. MATERIALS AND METHODS: Rabbit common femoral arteries were injured by mechanical overdilation and treated with buffer, viral control, or an adenovirus expressing AAT (Ad/AAT). After 3 and 28 days, intima-to-media (I/M) ratios were evaluated. Additionally, early changes in elastase inhibition potential (3 d), extracellular elastin and collagen content (3 d), and local macrophage and neutrophil infiltration (7 d) were determined. RESULTS: Ad/AAT significantly decreased neointima formation after mechanical dilation injury after 28 days: buffer controls exhibited mean I/M ratios of 0.76 +/- 0.06, whereas viral controls reached 0.77 +/- 0.09; in contrast, Ad/AAT reduced I/M ratios to 0.44 +/- 0.06. Both early elastin and collagen content were preserved in the Ad/AAT group relative to controls. The Ad/AAT group also reversed the local inflammation that characterized viral controls. CONCLUSIONS: This strategy demonstrates that local increases in elastase inhibition potential promote a neointima-resistant small-caliber artery, which may offer new promise in management of patients undergoing angioplasty.
Assuntos
Matriz Extracelular/metabolismo , Elastase Pancreática/antagonistas & inibidores , Túnica Íntima/efeitos dos fármacos , alfa 1-Antitripsina/genética , Angioplastia , Animais , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Técnicas de Transferência de Genes , Masculino , Elastase Pancreática/metabolismo , Coelhos , Túnica Íntima/fisiopatologia , alfa 1-Antitripsina/farmacologia , alfa 1-Antitripsina/uso terapêuticoRESUMO
OBJECTIVES: We studied enhancement of local gene delivery to the arterial wall by using an endovascular catheter ultrasound (US). BACKGROUND: Ultrasound exposure is standard for enhancement of in vitro gene delivery. We postulate that in vivo endovascular applications can be safely developed. METHODS: We used a rabbit model of arterial mechanical overdilation injury. After arterial overdilation, US catheters were introduced in bilateral rabbit femoral arteries and perfused with plasmidor adenovirus-expressing blue fluorescent protein (BFP) or phosphate buffered saline. One side received endovascular US (2 MHz, 50 W/cm2, 16 min), and the contralateral artery did not. RESULTS: Relative to controls, US exposure enhanced BFP expression measured via fluorescence 12-fold for plasmid (1,502.1+/-927.3 vs. 18,053.9+/-11,612 microm2, p < 0.05) and 19-fold for adenovirus (877.1+/-577.7 vs. 17,213.15+/-3,892 microm2, p < 0.05) while increasing cell death for the adenovirus group only (26+/-5.78% vs. 13+/-2.55%, p < 0.012). CONCLUSIONS: Endovascular US enhanced vascular gene delivery and increased the efficiency of nonviral platforms to levels previously attained only by adenoviral strategies.
Assuntos
Angioscopia , Artérias , Terapia Genética/métodos , Ultrassonografia de Intervenção , Animais , Masculino , CoelhosRESUMO
PURPOSE: Insulin-like growth factor-1 (IGF-1) is a potent chemoattractant to vascular smooth muscle cells (SMCs). The authors hypothesize that perivascular release of IGF-1 in vivo can direct migration of SMCs away from the lumen and reduce neointima formation in a rabbit model of arterial balloon injury. MATERIALS AND METHODS: Balloon angioplasty of the common femoral arteries was performed in adult male New Zealand White rabbits (n = 8 per treatment group) and controlled release microspheres delivering either IGF-1 or blank control treatment were implanted perivascularly at the angioplasty site prior to surgical closure. At 7 days, five arteries per group were harvested and cross-sections were subjected to anti-PCNA (proliferating cell nuclear antigen) immunostaining to determine the number and distribution of proliferating SMCs. At 28 days, the remaining three arteries per group were harvested and sections were evaluated for intima-to-media (I/M) ratios by means of VVG-Masson staining. One-way analysis of variance with Fisher protected least significant difference post hoc testing was used to determine statistical significance at P < .05. RESULTS: At 7 days, PCNA(+) medial SMCs assumed a significantly more peripheral (ie, further from lumen) distribution in the vessel wall with use of perivascular IGF-1 than with use of blank treatment (P < .05). Overall SMC proliferation was not significantly different, thus the change in distribution was likely due to directionally altered SMC migration. At 28 days, perivascular IGF-1 significantly decreased I/M ratios by 44% relative to control treatment (P < .05). CONCLUSIONS: Perivascular release of IGF-1 can directionally guide SMC migration away from the lumen and reduce neointima in the balloon-injured artery. This novel strategy might have implications in the development of antirestenosis therapies.
Assuntos
Angioplastia com Balão , Fator de Crescimento Insulin-Like I/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Túnica Íntima/crescimento & desenvolvimento , Animais , Divisão Celular , Movimento Celular/efeitos dos fármacos , Artéria Femoral/lesões , Fator de Crescimento Insulin-Like I/administração & dosagem , Masculino , Microesferas , Músculo Liso Vascular/fisiologia , Coelhos , Fatores de TempoRESUMO
Vascular endothelial growth factor (VEGF) can promote angiogenesis but may also exert certain effects to alter the rate of atherosclerotic plaque development. To evaluate this potential impact on plaque progression, we treated cholesterol-fed mice doubly deficient in apolipoprotein E/apolipoprotein B100 with low doses of VEGF (2 microg/kg) or albumin. VEGF significantly increased macrophage levels in bone marrow and peripheral blood and increased plaque area 5-, 14- and 4-fold compared with controls at weeks 1, 2 and 3, respectively. Plaque macrophage and endothelial cell content also increased disproportionately over controls. In order to confirm that the VEGF-mediated plaque progression was not species-specific, the experiment was repeated in cholesterol-fed rabbits at the three-week timepoint, which showed comparable increases in plaque progression.