Over-expression of Matrix Metalloproteinase-10 is Associated with Vascular Smooth Muscle Cell loss in Marfan Syndrome and Bicuspid Aortic Valve Aneurysm

Abstract

Thoracic aortic aneurysm associated with Marfan syndrome (MFS) or bicuspid aortic valve (BAV) is characterized by over-expression of matrix metalloproteinases (especially MMP-2 and MMP-9). Up-regulated MMP-10 has been linked to reduced cell–matrix interaction, cell detachment, dilation and rupture of blood vessels. We investigated MMP-10 expression in aortic aneurysm tissue and cultured VSMCs and its relation to VSMC apoptosis. Aortic tissue and cultured VSMCs were derived from subjects with MFS (five males, two females; 40 ± 22 years, mean ± S.D.) and BAV (five males, two females; 60 ± 16 years), and normal subjects (three males, six females; 44 ± 14 years). Caspase-3 was used as a marker of cells undergoing apoptosis. Specific staining of aortic tissue showed increased expression of MMP-10 in MFS and BAV (P < 0.05). Similar results were obtained in cultured VSMCs. In VSMCs characterized by cell shrinkage of cell and nuclear condensation there was enhanced staining of MMP-10. The same VSMCs showed caspase-3 labelling in alternate serial sections. The proportion of apoptotic VSMCs in aneurysm tissue was significantly increased in the aneurysm wall of patient groups compared to normal subjects (P < 0.05). Gelatin zymography showed no active form of MMP-10 and Western blot indicated the presence of the MMP-10 pro-form only with higher levels of expression in VSMC conditioned media from patients compared to normals (P < 0.05). The study suggests that expression of MMP-10 is related to progression of aortic wall aneurysm in MFS and BAV.