Jornal Vascular Brasileiro
http://www.jvascbras.org/article/doi/10.1590/1677-5449.180095
Jornal Vascular Brasileiro
Original Article

Histological changes secondary to use of anti-angiogenic therapy after interruption of vasa vasorum flow in the descending aorta: results in a porcine model

Alterações histológicas secundárias à interrupção dos vasa vasorum na aorta descendente com o uso de terapia antiangiogênica: resultados em modelo suíno

Cyro Castro Júnior; Adamastor Humberto Pereira

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Abstract

Abstract: Background: Anti-angiogenic regulators may have therapeutic implications for onset and progression of atherosclerosis.

Objectives: To demonstrate histological changes secondary to the use of bevacizumab in the aorta of pigs after interruption of flow in the vasa vasorum.

Methods: Twelve pigs were divided into two groups. The intercostal arteries of the descending aorta were dissected and ligated and wrapped with a polyvinyl chloride membrane. The treatment group received an intravenous dose of bevacizumab. After 15 days, the animals were euthanized and the aorta removed. Histological slides were prepared for control and treatment groups and for non-manipulated areas and analyzed for degree of angiogenesis, injury, inflammation, and intimal thickening. Data were expressed as mean (SD) of scores and groups were compared using the Mann-Whitney test. The Poisson distribution was used to calculate 95% confidence intervals for mean scores, in order to determine effect statistics.

Results: Bevacizumab had adverse effects on all treated pigs. The analysis using a Scale of Magnitudes for Effect Statistics showed a trend toward a decrease in angiogenesis [0.58 (1.79/-0.63)] and injury [0.55 (1.76/-0.66)] and an increase in inflammation [0.67 (1.89/-0.55)] with threshold moderate effects. There was no difference in intimal thickening [0 (1.19/-1.19)].

Conclusions: The medication exhibited a trend toward reduced angiogenesis and injury, but no reduction in the inflammatory process or intimal thickening of the aortic wall. These findings are in disagreement with studies that correlate neovascularization with increased migration of inflammatory cells. Bevacizumab exhibited toxicity in the porcine model.

Keywords

vasa vasorum, pathologic neovascularization, angiogenesis inhibitors

Resumo

Resumo: Contexto: Agentes antiangiogênicos podem ter implicações terapêuticas na progressão e manifestação da aterosclerose.

Objetivos: Demonstrar a alteração histológica secundária ao uso de bevacizumabe na aorta descendente de suínos submetida à interrupção dos vasa vasorum.

Métodos: Em doze suínos, divididos em dois grupos, foi realizada dissecção da aorta torácica, além de ligadura das artérias intercostais e proteção com polivinil. O grupo tratamento recebeu dose endovenosa de bevacizumabe. Após 15 dias, os animais foram sacrificados para retirada da artéria e preparo das lâminas histológicas dos grupos tratamento, controle e áreas não manipuladas para análise quanto aos graus de angiogênese, injúria, inflamação e espessamento intimal. A análise estatística foi conduzida através da média e do desvio padrão dos escores. As comparações entre os grupos foram realizadas pelo teste de Mann-Whitney. A distribuição de Poisson calculou os intervalos de confiança de 95% para as médias, a fim de determinar o efeito estatístico.

Resultados: O bevacizumabe causou efeitos adversos em todos os suínos tratados. As variáveis analisadas através da Escala de Magnitude para Efeito Estatístico demonstraram tendência de redução da angiogênese [0,58 (1,79/-0,63)] e da injúria [0,55 (1,76/-0,66)] e aumento da inflamação [0,67 (1,89/-0,55)] no limite do moderado. Não ocorreu diferença no espessamento intimal [0 (1,19/-1,19)].

Conclusões: A medicação utilizada mostrou tendência de redução da angiogênese e da injúria, mas não reduziu o processo inflamatório ou o espessamento intimal da parede arterial. Esses achados contrariam estudos que correlacionam a neovascularização com o aumento da migração de células inflamatórias. O bevacizumabe mostrou toxicidade no modelo suíno.
 

Palavras-chave

vasa vasorum, neovascularização patológica, inibidores da angiogênese

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