A German pathologist first described defects in the elastic tissues of human arteries over one hundred years ago. Much evidence now supports the involvement of these elastic tissue defects (ETDs) in the initiation and progression of atherosclerosis, although this association is not well accepted. Recent research has determined that the migration of medial smooth muscle cells into the intima (and therefore the start of the atherosclerotic process) is initiated in an attempt to repair these defects and in addition, that there is a correlation between the extent of intimal thickening and the degree of elastic tissue disruption. The Brown Norway (BN) strain appears to have an increased predilection, having a significantly greater incidence of ETDs within the caudal and renal arteries and the abdominal aorta compared with other rat strains. These defects appear morphologically identical to those observed in the arteries of young humans. The purpose of this study was to determine the magnitude of the genetic and environmental components in the formation of these ETDs in the aorta.
Previous studies have demonstrated that the spontaneous formation of elastic tissue defects in the abdominal aorta of the Brown Noway rat is a genetically inherited phenotype, passed from parent to offspring in an autosomal dominant manner. Following crossbreeding of the BN rat with four other strains (two hypertensive and two normotensive) it was determined that, although the inheritance mode of the ETD phenotype followed an autosomal dominant pattern, the expression or penetrance of this phenotype was reduced in F₁ all crossbred groups. Moreover, the early postnatal growth profile of the F₁ pups appeared to be differentially associated with defect formation. To further examine the relationship between aortic ETDs and birthweight, a well-studied model of in utero growth restriction was investigated in the BN rat. On day 18 of a 23-day gestation the uterine arteries were ligated, which resulted in offspring that were 14% smaller than un-operated control pups. This short-term insult resulted in significantly increased numbers of ETDs in growth-restricted animals at 8 weeks of age, an effect that was also observed in 16-week old males. The effect of in utero growth restriction on ETDs in the guinea pig and ApoE knockout mouse was also examined, to determine if ETDs (and subsequent early atherosclerotic events) may be influenced by the exposure to a growth-restricting event in utero. Despite this work leading to the novel characterisation of ETDs in the guinea pig aorta, the growth restricting surgery resulted in poor maternal and pup outcomes, which limited the conclusions that could be drawn from these studies.
Furthermore, microarray techniques were employed to examine changes in aortic gene expression following growth restriction, by comparing amplified mRNA extracts from 8-week old growth restricted BN pup aortas with extracts from a group of average birthweight, un-operated BN pups. In combination, these studies propose both genetic inheritance and the in utero environment regulate elastic tissue defect phenotype, which in turn potentially affects the initiation and progression of early atherosclerosis.
| Identifer | oai:union.ndltd.org:ADTP/217484 |
| Date | January 2006 |
| Creators | Pascoe, Katie Clare, n/a |
| Publisher | University of Otago. Dunedin School of Medicine |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Katie Clare Pascoe |
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