The Role of Transglutaminases in the Development of Abdominal Aortic Aneurysms

Abdominal aortic aneurysms (AAA) are dilatations of the abdominal aorta that are prone to rupture with fatal consequences. AAAs (diameter >3cm) are present in ~4% of men aged >65years. AAA formation is initiated with the loss of medial elastin. Responses to this include synthesis of tropoelastin and deposition of collagen. Dilatation occurs following degradation of this collagen, secondary to release and activation of matrix metalloproteinases (MMPs) by invading macrophages. Elastin is strengthened and protected from proteolysis by cross-linking. Transglutaminases (TGs) introduce cross-links between protein chains and have been implicated in arterial repair; TG2 has been shown to be induced early in experimental aneurysm development. The literature suggests that TG2 and the homologous enzyme FXIII-A may act cooperatively or may compensate for each other in the face of deficiency. We have bred TG2-/-, FXIII-A-/- and TG2-/-.FXIII-A-/- double knockout (DKO) mice to characterise their basal vessel structure and function and investigate their susceptibility to aneurysm formation. This work has shown that both FXIII-A and TG2 are involved in the maintenance of basal vessel integrity and that aortic permeability is increased in mice lacking FXIII-A. In the absence of the repair function of TG2, the DKO mice develop extensive cardiovascular fibrosis and exhibit decreased vessel tension. We have not seen evidence of a clear protective effect of TG2, however our DKO animals showed an (unexpected) decreased propensity to aneurysm formation. In an extended model there is evidence that aneurysm initiation and progression occur by different mechanisms and that TG2 plays a role in prevention of the latter. This thesis has also shown that TG2 and/or FXIII-A are not essential for vascular calcification. The results presented here help to define the common and distinct functions of FXIII-A and TG2 in arterial structure and function, and provide evidence in their evaluation as potential therapeutic targets.