Am J Physiol Heart Circ Physiol. 2017 Aug 1;313(2):H446-H456. doi: 10.1152/ajpheart.00712.2016. Epub 2017 May 26.
Mechanical behavior and matrisome gene expression in the aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice
STAICULESCU MC, KIM J, MECHAM RP, WAGENSEIL JE.
Mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysm and dissection (TAAD). Mice that do not express Lox (Lox-/-) die soon after birth and have 60% and 40% reductions in elastin- and collagen-specific crosslinks, respectively. LOX inactivation could also change the expression of secreted factors, structural matrix, and matrix-associated proteins that constitute the aortic matrisome. We hypothesize that the absence of Lox will change the mechanical behavior of the aortic wall due to reduced elastin and collagen crosslinking and alter the expression levels of matrisome and smooth muscle cell (SMC) genes in a vascular location-specific manner. Using fluorescence microscopy, pressure myography, and gene set enrichment analysis (GSEA), we visualized the microarchitecture, quantified the mechanical behavior, and examined matrisome and SMC gene expression from ascending (AA) and descending aortas (DA) from newborn Lox+/+ and Lox-/- mice. Even though Lox-/- AA and DA have fragmented elastic laminae and disorganized SMCs, the unloaded outer diameter and wall thickness are similar to Lox+/+ AA and DA. Lox-/- AA and DA have altered opening angles, circumferential stresses, and circumferential stretch ratios; however only Lox-/- AA has increased pressurized diameters and tangent moduli. GSEA shows upregulation of the ECM regulators gene set in Lox-/- AA and DA, as well as differential expression of secreted factors, collagens, ECM affiliated, ECM glycoproteins, and SMC cell cycle gene sets that depend on Lox genotype and vascular location. These results provide insight into the local chemo-mechanical changes induced by Lox inactivation that may be important for TAAD pathogenesis.