Targeting of MMP-13 prevents aortic aneurysm formation in Marfan mice

Abstract

Fibrillin-1 assembles into microfibrils that not only define the structural integrity and biomechanics of the aorta but also target and sequester growth factors within the extracellular microenvironment of aortic resident cells. To better understand how dominant negative effects on fibrillin microfibril stability manifest in growth factor driven aortic disease, we analyzed early events of aortic aneurysm formation within the first two weeks of postnatal life in the dominant negative Fbn1 GT8 Marfan mouse model. Echocardiography analysis of homozygous GT8 Fbn1 mice showed significant aortic root enlargement within the second week of postnatal life which correlated with the onset of fibrillin-1 fiber degradation, aberrantly increased BMP activity and upregulated transcript levels of the collagenase MMP-13. We also found the aortic collagen network structurally disturbed where the mutant GT8-fibrillin-1 was detected. Genetic ablation or pharmacological inhibition of MMP-13 in Fbn1 GT8 Marfan mice prevents aortic root dilatation implicating the relevance of this mechanism in aortic aneurysm formation in Marfan syndrome.