Mechanical behavior and matrisome gene expression in the aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice

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 cross-links, respectively. LOX inactivation could also change the expression of secreted factors, the structural matrix, and matrix-associated proteins that constitute the aortic matrisome. We hypothesized that absence of Lox will change the mechanical behavior of the aortic wall because of reduced elastin and collagen cross-linking 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, we visualized the microarchitecture, quantified the mechanical behavior, and examined matrisome and SMC gene expression from ascending aortas (AAs) and descending aortas (DAs) from newborn Lox^+/+ and Lox^-/- mice. Even though Lox^-/- AAs and DAs have fragmented elastic laminae and disorganized SMCs, the unloaded outer diameter and wall thickness were similar to Lox^+/+ AAs and DAs. Lox^-/- AAs and DAs have altered opening angles, circumferential stresses, and circumferential stretch ratios; however, only Lox^-/- AAs have increased pressurized diameters and tangent moduli. Gene set enrichment analysis showed upregulation of the extracellular matrix (ECM) regulator gene set in Lox^-/- AAs and DAs as well as differential expression of secreted factors, collagens, ECM-affiliated proteins, ECM glycoproteins, and SMC cell cycle gene sets that depend on the Lox genotype and vascular location. These results provide insights into the local chemomechanical changes induced by Lox inactivation that may be important for TAAD pathogenesis. NEW & NOTEWORTHY Absence of lysyl oxidase (Lox) causes thoracic aortic aneurysms. The aortic mechanical behavior of Lox^-/- mice is consistent with reduced elastin and collagen cross-linking but demonstrates vascular location-specific differences. Lox^-/- aortas show upregulation of matrix remodeling genes and location-specific differential expression of other matrix and smooth muscle cell gene sets.