Atherosclerotic and restenotic lesions develop as a result of an excess inflammatory response to vascular injury. Glucocorticoid hormones have widely-recognised anti-inflammatory and anti-proliferative properties which appear to make them ideal candidates for inhibition of vascular lesion development. Indeed, administration of glucocorticoids to experimental animals does inhibit the growth of vascular lesions in some models. In addition, glucocorticoids are currently being trialled clinically as anti-restenotic agents. However, glucocorticoid excess in patients, either as a result of Cushing’s syndrome or chronic steroid therapy, is associated with enhanced CVD risk. Therefore, the effects of glucocorticoids on vascular lesion development remain imperfectly understood. The overall objective of these studies was to explore the influence of endogenous and exogenous glucocorticoids on vascular lesion development using murine models of atherosclerosis (ApoE-/- mice fed a “western” diet) and neointimal hyperplasia (wireinduced femoral artery injury). The work described in this thesis addresses the hypothesis that glucocorticoids are pro-atherogenic, yet anti-restenotic. Mice were bilaterally adrenalectomised to investigate the role of endogenous glucocorticoids on vascular lesion development. Removal of the adrenal glands had no influence on atherogenesis or neointima development. The influence of exogenous glucocorticoids on lesion development was assessed by orally administering dexamethasone (0.1 or 0.8mg/kg/day). Atherosclerotic lesion burden was augmented by dexamethasone administration. Conversely, fibro-proliferative neointimal proliferation was inhibited by dexamethasone. However, this effect was obscured by thrombotic lesion development. It was proposed that this thrombotic effect is attributable to increased plasminogen activator inhibitor-1 (PAI-1), which was tested using PAI-1 deficient mice. Although PAI-1 was found to mediate the systemic pro-thrombotic effect of dexamethasone, it is not required for the enhanced development of thrombotic lesions at the site of intra-luminal injury. These results suggest that physiological levels of endogenous glucocorticoids play a limited role in vascular lesion development. Conversely, although exogenous glucocorticoids inhibit fibro-proliferative intimal hyperplasia, they appear to have significant detrimental influences on lesion development, augmenting atherosclerosis and inducing thrombotic neointimal lesion formation following vascular injury. Further research is therefore required to improve the cardiovascular outcome of patients requiring glucocorticoid therapy and for the use of glucocorticoids as antirestenotic agents.

As lesões vasculares estão entre as anormalidades congênitas e neonatais mais comuns. Cerca de 60% estão localizadas na região da cabeça e pescoço. A identificação e a classificação adequadas de cada tipo de lesão, tem um impacto direto no diagnóstico e, no tratamento destes pacientes. A técnica de Tomografia por Coerência Óptica (Optical coherence tomography: OCT) obtém imagens em alta resolução, geradas em tempo real que permitem visualizar de forma não invasiva, estruturas celulares e extracelulares, com uma resolução espacial da ordem de 10μm, que é 20 vezes maior que a de um ultrassom, aproximando-se do nível histológico convencional, razão pela qual é considerada biópsia óptica. Com o objetivo de fornecer imagens que possibilitassem avaliar as diferenças na arquitetura dos vasos em diferentes tipos de lesões localizadas, no tecido cutâneo e na mucosa, em regiões da cabeça e pescoço, foram tomadas imagens de lesões de 27 pacientes usando um sistema de OCT com Doppler (1325nm). Os resultados deste estudo clínico comprovaram a viabilidade da OCT permitindo distinguir entre a pele normal e a pele com lesão. Na má-formação capilar, os vasos sanguíneos tiveram diâmetro médio de 114\\μm ± 92μm e apresentaram uma profundidade média de 304 μm ± 99 μm. Os hemangiomas apresentaram vasos sanguíneos com diâmetro médio de 39μm ± 19 μm e profundidade média de 298 μm ± 133 μm. Nas lesões diagnosticadas pelo clínico como Hemangioma da mucosa labial, medimos diâmetro médio dos vasos de 45μm ± 16 μm com profundidade média de 520,5μm ± 189,5μm. Na má-formação linfática de lábio, os vasos sanguíneos apresentaram diâmetro médio de 157,5μm ± 90μm e, uma profundidade média 695μm ± 136μm. Na má-formação vascular de lábio, os vasos sanguíneos apresentaram diâmetro médio de 128μm±63μm e, uma profundidade média 689 μm ± 217μm. Com estas informações obtidas das imagens de OCT indicando fluxo, foi possível avaliar diferenças peculiares da lesão de cada paciente, promovendo o diagnóstico diferencial das lesões vasculares da superfície tecidual da pele e mucosa oral. / Vascular lesions are among the most common congenital and neonatal abnormalities. About 60% are in the head and neck region. The proper identification and classification of each type of lesion has a direct impact on the diagnosis and consequently on the treatment of these patients. The Optical Coherence Tomography (OCT) technique obtains high resolution, real time generated images that allow non-invasive visualization of bio tissue structures with a spatial resolution of the order of 10μm, which is 20 times greater than that of an ultrasound, approaching the conventional histological level. That is why it is considered an optical biopsy. In this thesis, images of lesions from 27 patients were obtained using a Doppler OCT system operating at 1325nm, with the purpose of providing images that allowed to evaluate the differences in the architecture of the vessels in different types of lesions located in the cutaneous and mucosa tissue in head and neck regions. The results of this clinical study proved the viability of OCT to distinguish between normal skin and lesioned skin. In vascular malformation, the blood vessels had an average diameter of 114 μm ± 92 μm and had a mean depth of 304,3 μm ± 99 μm. The skin hemangiomas had blood vessels with a mean diameter of 38,6 μm ± 19 μm and a mean depth of 297,8 μm ± 132 μm. In the lesions clinically diagnosed as oral mucosa hemangioma (lips), the mean vessel diameter was 45 μm ± 16 μm and a mean depth of 520,5 μm ± 189,5 μm. In lip lymphatic malformation, the blood vessels had a mean diameter of 157,5 μm ± 90 μm and a mean depth of 695 μm ± 136 μm. In lip vascular malformation, the blood vessels had a mean diameter of 128 μm ± 63 μm and a mean depth of 689 μm ± 217 μm. With this information obtained from the Doppler OCT images indicating flow, it was possible to evaluate peculiar differences of the lesion of each patient, promoting the differential diagnosis of vascular lesions of the tissue surface of the skin and oral mucosa.