Congenital thoracic aortic aneurysm is a complication of bicuspid aortic valve disease (BAV). BAV results from congenital fusion of two valvular cusps. The TGFβ signaling pathway plays a key role in mediating aneurysm formation. We examined the relationship between aneurysm formation and expression of effector molecules, including TGFβ sequestration proteins and matrix metalloproteinases (MMPs).
The levels of protein expression in 8 human aneurysmal BAV aortas and 6 controls were examined by immunohistochemistry. TGFβ expression was found to be elevated (2.5x normal). Inactive TGFβ is stored within the extra-cellular matrix via sequestration proteins bound to the microfibrillar protein, fibrillin. Alterations in the pattern of expression of these proteins were predicted to result in release of active TGFβ. Specifically, MAGP-1 (promotes TGFβ release) was found to be elevated, while LTPB-1 (promotes TGFβ binding) was found to be decreased. Paradoxically, fibrillin-4 (promotes TGFβ binding) was found to be elevated (p < 0.05).
Excessive MMP activity will result in pathological matrix remodeling and weakening of the aortic wall. The BAV specimens displayed elevated MMP-2 expression (2.6x normal) and MMP-9 expression (1.5x normal), and, paradoxically, decreased MMP-3 expression (0.5x normal) (p < 0.05). Additionally, regional differences were observed, with the greatest change in expression occurring in the adventitia for TGFβ (3.4x normal) and MMP-9 (2x normal).This study suggests increased TGFβ activity contributes to the formation of genetic thoracic aneurysms in BAV patients. Excessive TGFβ signaling then results in pathological matrix remodeling, mediated via elevated levels of MMP-2 and MMP-9, leading to destruction of collagen and elastin, and progression of dilation. Paradoxically, decreased MMP-3 may represent a compensatory mechanism that attempts to reduce overall pathological MMP activity, in order to limit damage to the aortic wall.