Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Timothy Regnault

2nd Supervisor

Dr. Bryan Richardson

Joint Supervisor

Abstract

The effect of intrauterine hypoxia on arterial development was evaluated with use of large and small animal models. Analyses included expression and deposition of extracellular matrix (ECM) proteins, differentiation and proliferation of vascular smooth muscle cells (VSMCs), intima formation and wall thickening. A comprehensive investigation of possible molecular, mechanical and hormonal mediators of altered arterial development was afforded by a sheep model with both acute and chronic hypoxemia studies, whereas a guinea pig model allowed for long-term study. Our findings show that chronically hypoxic fetal sheep and intrauterine growth restricted (IUGR) guinea pigs exhibit a reduction in elastic fibre content of the aorta. In adulthood, the deficiency in aortic elastic fibre content in growth restricted guinea pig offspring was amplified compared to the subtle changes observed in late fetal life. In severely hypoxic fetal sheep, more marked reduction in elastin content occurred with increases in wall thickness and VSMC content. Increased collagen paralleled elevated mRNA levels of procollagen I and transforming growth factor beta (TGF-β 1). Matrix metalloproteinase-2 (MMP-2) mRNA levels were inversely correlated with fetal arterial oxygen saturation and expression of its activator, membrane-type MMP (MTI-MMP), was elevated in severely hypoxic sheep. Marked neointima formation was also apparent in severely hypoxic fetuses concomitant with increased mRNA levels of E-selectin, indicating endothelial inflammation. These structural and molecular changes of the aorta in chronically hypoxic ovine fetuses occurred without changes in pressure or circulating cortisol levels. Further, while the hypoxic sheep showed no change in VSMC maturation, aortae of IUGR guinea pig fetuses and offspring had increased content of myosin heavy chain B (MHC-B), a marker iv

of undifferentiated VSMCs. Aortae of growth impaired guinea pig offspring exhibited a left shift in the length-tension curve as measured ex vivo. Thus altered aortic development in association with chronic hypoxia or IUGR leads to persistent structural abnormalities and reduced compliance in later life. In contrast, acute hypoxic study in fetal sheep demonstrated increased elastin content of the carotid artery in association with intermittent hemodynamic changes and elevated cortisol and thus highlight that beneficial adaptations are possible under certain intrauterine insults.

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