Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta, although in both ascending and descending aortae, changes in vessel wall structure, smooth muscle cell number, and inflammatory cell recruitment differed between WT and mutant animals. Studies with isolated cells revealed that M292R-mutant LOX is retained in the endoplasmic reticulum and ultimately cleared through an autophagy/proteasome pathway. Because the mutant protein does not transit to the Golgi, where copper incorporation occurs, the protein is never catalytically active. These studies show that the M292R mutation results in LOX loss of function due to a secretion defect that predisposes the ascending aorta in mice (and by extension humans with similar mutations) to arterial dilation when exposed to risk factors that impart stress to the arterial wall. © 2019, American Society for Clinical Investigation.