RESUMO
OBJECTIVES: The effects of direct intramyocardial injection of the plasmid encoding vascular endothelial growth factor (phVEGF165) in the border zone of myocardial infarct tissue in rat hearts were investigated. BACKGROUND: Controversy exists concerning the ability of VEGF to induce angiogenesis and enhance coronary flow in the myocardium. METHODS: Sprague-Dawley rats received a ligation of the left coronary artery to induce myocardial infarction (MI). At 33.1 +/- 6.5 days, the rats were injected with phVEGF165 at one location and control plasmid at a second location (500 microg DNA, n = 24) or saline (n = 16). After 33.1 +/- 5.7 days, the hearts were excised for macroscopic and histologic analysis. Regional blood flow ratios were measured in 18 rats by radioactive microspheres. RESULTS: phVEGF165-treated sites showed macroscopic angioma-like structures at the injection site while control DNA and saline injection sites did not. By histology, 21/24 phVEGF165-treated hearts showed increased focal epicardial blood vessel density and angioma-like formation. Quantitative morphometric evaluation in 20 phVEGF165-treated hearts revealed 44.4 +/- 10.5 vascular structures per field in phVEGF165-treated hearts versus 21.4 +/- 4.7 in control DNA injection sites (p < 0.05). Regional myocardial blood flow ratios between the injection site and noninfarcted area did not demonstrate any difference between phVEGF,165-treated hearts (0.9 +/- 0.2) and saline-treated hearts (0.7 +/- 0.1). CONCLUSIONS: Injection of DNA for VEGF in the border zone of MI in rat hearts induced angiogenesis. Angioma formation at the injection sites did not appear to contribute to regional myocardial blood flow, which may be a limitation of gene therapy for this application.
Assuntos
Modelos Animais de Doenças , Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/uso terapêutico , Terapia Genética/métodos , Neoplasias Cardíacas/induzido quimicamente , Hemangioma/induzido quimicamente , Linfocinas/genética , Linfocinas/uso terapêutico , Infarto do Miocárdio/terapia , Neovascularização Fisiológica/efeitos dos fármacos , Plasmídeos/genética , Plasmídeos/uso terapêutico , Animais , Circulação Coronária/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fatores de Crescimento Endotelial/efeitos adversos , Terapia Genética/efeitos adversos , Neoplasias Cardíacas/patologia , Hemangioma/patologia , Injeções , Linfocinas/efeitos adversos , Infarto do Miocárdio/patologia , Plasmídeos/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
The tumor-initiating potency of three simple alkyl carbamates and mono-N-substituted ethyl carbamates was examined in Hall strain mice. The binding of 14C-labeled carbamates of DNA was measured in Crackenbush mice. Ethyl carbamate was the most potent carcinogen for the epidermis, liver, and lung, followed by its N-alkyl derivatives. Methyl carbamate was without effect but n-propyl and n-butyl were possible carcinogens. The ethyl esters bound to a greater extent to DNA in liver and skin than the methyl, n-propyl, and n-butyl esters and only this binding persisted. A preliminary application of croton oil increased the yield of skin tumors but not of liver or lung tumors. It also increased the binding of the alkyl carbamates to DNA in skin, the increase being greatest with ethyl carbamate. The binding persisted longer in treated than in non-croton oil-treated mice.