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Title: Role of decorin in control of endothelial cell behaviour
Author: Fiedler, Lorna
ISNI:       0000 0004 2750 7944
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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Angiogenesis is a complex process regulated by co-ordination of extracellular matrix (ECM) and growth factor signalling (via integrins and growth factor receptors respectively). Dysregulated angiogenesis contributes to disease pathology and progression, while an adequate blood supply is crucial for successful tissue repair and reconstruction. Thus an understanding of the mechanisms by which ECM controls angiogenesis would contribute to development of therapeutic strategies. Decorin is a small leucine-rich repeat proteoglycan consisting of a core protein and a single glycosaminoglycan. Decorin has been reported to contribute to ECM organisation through interaction with numerous ECM components, including collagen types I, VI, XII and XIV, fibronectin, thrombospondin, tropoelastin and tenascin-X. Further, decorin influences growth factor activity, interacts with a2pl integrin, and can activate growth factor receptors. In the absence of decorin, angiogenesis is dysregulated however it is not known which of these interactions are responsible. This thesis investigates the role of decorin interactions with collagen type I, a2pl integrin (a collagen I receptor), and the IGF-I receptor in modulating endothelial cell behaviour. This thesis demonstrates that both collagen-bound and soluble decorin enhance endothelial cell adhesion and migration, and that the latter may involve activation of the IGF-I receptor, and the small GTPase Rac, by decorin. In accordance with this, decorin induced morphological changes consistent with activation of small GTPases. Further, decorin interacts with a2pl integrin via the GAG moiety, and may influence integrin activity in an allosteric manner, although the intact proteoglycan is required for modulation of endothelial cell behaviour. It was also demonstrated that decorin supports a2pl integrin activation in the presence of the specific inhibitor rhodocetin. Additionally, decorin activates transcription factors associated with long-term cell survival and quiescence. Together, these data implicate decorin as an important regulator of several aspects of angiogenesis pertinent to establishment of mature neo-vessels.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available