Fibulin-4 and Lysyl Oxidase Cooperate to Maintain Arterial Wall Integrity in Large but not Small Vessels

Fibulin-4 (FBLN4) is an extracellular matrix protein essential for elastic fiber assembly in large conduit arteries. While its exact role in the process remains unknown, it is hypothesized that, through binding lysyl oxidase (LOX), FBLN4 facilitates elastin crosslinking and mature elastic fiber formation. To assess whether FBLN4 and LOX interact in the process of elastic fiber formation in vivo, we took a genetic approach where we bred recently characterized mice carrying a disease-causing mutation in Fbln4 (Fbln4E57K) with LOX insufficient (Lox+/−) mice and examined the consequences of LOX insufficiency on the cardiovascular system of Fbln4E57K mice. By 3–4 months of age Fbln4E57K;Lox+/− mice were similar in size to Fbln4E57K mice and littermates. Ascending aortic aneurysms, which were incompletely penetrant and confined to the ascending aorta in Fbln4E57K mice were significantly worsened by LOX insufficiency as they were fully penetrant and extended from the aortic root through the aortic arch in Fbln4E57K;Lox+/− mice. Additionally, arterial tortuosity and elastic fiber fragmentation of large conduit arteries were exacerbated by LOX insufficiency. Interestingly, muscular arteries remained intact. Fbln4E57K;Lox+/− mice had significant cardiac hypertrophy and widening of the pulse pressure that was due to lower diastolic blood compared to Fbln4E57K mice. The cardiac hypertrophy and decrease in diastolic blood pressure are likely a consequence of worsened aortic regurgitation as large artery stiffness was not exacerbated by LOX insufficiency in Fbln4E57K mice. In summary, LOX insufficiency exacerbated the vascular phenotype seen in mice with mutant FBLN4 suggesting that there is a functional interaction between the two molecules. Interestingly, elastic fiber formation was unaffected in muscular arteries raising the possibility that the process of elastic fiber assembly, previously thought to be the same in all elastic tissues, may differ between vascular beds. Support or Funding Information NIH, NHLBI - 1K08HL135400 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.