부산대학교 도서관

Abdominal aortic aneurysms (AAAs) are a pathological dilation of the aorta, causing over 2,000 deaths per year in the UK. There is currently no pharmacological treatment for this disease. In AAAs, vascular smooth muscle cells (VSMCs) undergo a phenotypic switch from a contractile phenotype, in which there are high levels of contractile proteins such as α-smooth muscle actin (α-SMA) and calponin, into a proliferative and migratory synthetic phenotype. The focus of this thesis was on manipulating VSMC phenotype to develop a therapeutic treatment for AAAs. Platelet-derived growth factor-BB (PDGF-BB) induced a synthetic phenotype in vitro in human aortic smooth muscle cells (HAoSMCs), the most suitable cell type for extrapolating findings to human AAAs. This provided an in vitro model which was used to test the capacity of various treatments to revert HAoSMCs from this synthetic phenotype into a contractile phenotype. Peroxisome proliferator activated receptors (PPAR) and retinoic acid receptors (RAR) have previously been shown to be involved in VSMC phenotypic switch in vitro, but they had not previously been investigated in HAoSMCs . Neither PPAR-δ agonist GW501516 nor PPAR-δ target protein angiopoietin-like 4 (ANGPTL4) reverted HAoSMCs into a contractile phenotype. On the other hand, RAR agonist retinoic acid (RA) maintained HAoSMCs in a contractile phenotype. The effect of RA in vivo was investigated in an Angiotensin-II (Ang-II) infusion mouse model of AAA. RA partially supressed the Ang-II-induced synthetic phenotype in male mice but not female mice. RA had no effect on AAA incidence, but in male mice RA partially supressed Ang-II-induced aortic remodelling which is considered an early stage of AAA development. These results demonstrate that RA maintains HAoSMCs in a contractile phenotype in vitro and in vivo. Future work is required to assess whether this modulation of phenotype is beneficial for the suppression of AAA development in humans.