Mutation in the matricellular gene fibulin-4 leads to endothelial dysfunction in resistance arteries

Abstract

Mutations in fibulin-4 (FBLN4), a matricellular gene required for extracellular matrix (ECM) assembly, result in autosomal recessive cutis laxa type 1B (ARCL1B), a syndrome characterized by loose skin, aortic aneurysms, pulmonary emphysema and skeletal abnormalities. Fbln4E57K/E57K mice recapitulated the phenotypes observed in ARCL1B. In particular, they exhibited ascending aortic aneurysms, elastic fiber fragmentation and increased stiffness in large arteries, and systolic hypertension. Surprisingly however, internal elastic laminae of small resistance and muscular arteries were intact. Here, we show that the increased pulsatile flow resulting from the structural abnormalities and increased stiffness of conduit arteries in Fbln4E57K/E57K mice leads to increased shear stress, a highly oxidative environment, and endothelial dysfunction related to reduced nitric oxide bioavailability in resistance mesenteric arteries. These data have significant implications, not only for the basic biology of ECM assembly along the arterial tree, but also for the clinical consequences of large artery stiffness on the microcirculation.