Key result
The Fbln4E57K/E57K mutation leads to impaired endothelial-dependent vasodilation in mesenteric arteries due to reduced nitric oxide bioavailability and increased oxidative stress.
Why the study?
Does the Fbln4 E57K/E57K mutation cause endothelial dysfunction in resistance arteries in mice?
Does the Fbln4 E57K/E57K mutation cause endothelial dysfunction in resistance arteries in mice?
The Fbln4 E57K/E57K mutation leads to large artery stiffness and increased pulsatile flow, which causes increased shear stress, oxidative stress, and endothelial dysfunction in downstream resistance arteries.
Fbln4 E57K/E57K mice model ARCL1B aneurysms; leaves open ECM-targeted therapies for human aortopathy.
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. Fbln4 E57K/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 Fbln4 E57K/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.
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Lin et al. (2022) studied Autosomal recessive cutis laxa type 1B (ARCL1B) model / Fbln4 mutation. Fbln4E57K/E57K mutation vs. Wild-type littermates was evaluated on Endothelial-dependent vasodilation in response to acetylcholine. The Fbln4E57K/E57K mutation leads to impaired endothelial-dependent vasodilation in mesenteric arteries due to reduced nitric oxide bioavailability and increased oxidative stress.
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