Khurana, Rohit; (2004) Mechanism of arterial neointima formation: Study of the effects of angiogenic factors in vivo. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Arterial thickening due to neointimal vascular smooth muscle cell (VSMC) and macrophage accumulation is an important early stage in atherosclerosis. Angiogenesis and angiogenic cytokines have been implicated in neointima formation, but their roles are not clearly understood. The aim of this thesis was to examine the effects of angiogenic factors on the growth and cellular composition of arterial neointimal lesions in an animal model. Lesion formation was induced by the placement of a biologically inert collar around the carotid artery of rabbits. This induced the formation of localised lesions containing predominantly VSMCs with and without macrophages, in animals maintained on normal and hypercholesterolaemic diets, respectively. This model facilitates localized gene delivery and allows the biological influence of the endothelium to contribute to the observed effects, since it remains anatomically intact. Initially, the cellular composition of lesions was characterized on normal and cholesterol-enriched diets. Transfer of genes encoding angiogenic factors was performed using either low efficiency liposome-mediated or high efficiency adenoviral (Ad-) gene transfer, and mRNA and protein expression of transgene products was evaluated. Low efficiency liposome-mediated gene transfer of the potent angiogenic factor, vascular endothelial growth factor-A (VEGF-A), reduced intimal thickening, macrophage infiltration and endothelial vascular cell adhesion molecule (VCAM-1) expression in hypercholesterolaemic rabbits without significantly increasing angiogenesis. In contrast, high efficiency Ad.VEGF-A transduction of collared arteries caused little significant change in either intimal thickening or macrophage content of lesions. Transfer of Ad.Placental Growth Factor-2 (P1GF2), a factor related to VEGF-A, increased neointimal macrophage infiltration and thickening, endothelial VCAM-1 expression and angiogenesis in the collared arteries of hypercholesterolaemic rabbits. The effect of proline-arginine rich peptide (PR39), a natural mammalian peptide that induces angiogenesis via inhibition of proteasome-mediated degradation of hypoxia inducible factor, was also studied. Ad.PR39 increased angiogenesis and increased intimal thickening. Inhibition of both VEGF and fibroblast growth factor pathways abolished the effects of PR39. Though a striking correlation was observed between the degree of intimal thickening and adventitial neovascularisation, the results indicate that PR39-induced neointima formation in this model has both angiogenesis-independent and -dependent phases. A direct chemotactic effect on VSMCs by both VEGF and PR39 was also demonstrated. In summary, periadventitial gene delivery of angiogenic factors exerted profound effects on neointimal lesion formation in the collar model, as follows: (i), A concentration-dependent effect of VEGF-A in the regulation of neointima formation, (ii), PIGF induces atherogenic changes in the arterial wall and (iii). Studies with PR39 suggest that intimal thickening has two phases, an angiogenesis-independent phase and a later angiogenesis-dependent phase. These results reveal a complex interaction between angiogenic factors and neointima formation and are likely to have implications for the therapeutic use of angiogenic cytokines for ischaemic cardiovascular disease.

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