Blocking Compensatory Matrix Cross-Linking Accelerates ThoracicAortopathy in a Mouse Model of Marfan Syndrome

Abstract

Mechanical homeostasis plays a central role in promoting and preserving optimal structure and function in the adult aorta. Although pathogenic variants can compromise homeostatic processes, it appears that intramural cells yet attempt to compensate for some genetically induced changes. In particular, lysyl oxidase is higher in the adult Marfan aorta compared with the age-matched control aorta. Here, we block lysyl oxidase in adult Fbn1C1041G/+ Marfan syndrome mice after stimulating aortic disease progression via induced hypertension. Whereas hypertension alone increases aortic dilatation, concurrent blocking of lysyl oxidase results in a dramatic increase in disease severity, driving an otherwise mild aortic phenotype in adult male Fbn1C1041G/+ Marfan mice to aneurysmal dilatations as well as dissection and rupture, with frequent premature death. Deposition and cross-linking of fibrillar collagens, among other extracellular matrix constituents, can represent a protective compensation against severe disease in the Marfan aorta. The present study emphasizes the need clinically to avoid compromising new collagen deposition and suggests that strategies to augment collagen cross-linking could be beneficial.