Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries.

Science Advances
Carmen M HalabiRobert P Mecham

Abstract

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We foun...Continue Reading

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Citations

Dec 10, 2017·Journal of Biomechanical Engineering·Maria Gabriela EspinosaJessica E Wagenseil
Nov 10, 2018·American Journal of Physiology. Heart and Circulatory Physiology·J D Humphrey, G Tellides
Mar 7, 2020·Current Opinion in Hematology·Carmen M Halabi, Beth A Kozel
May 29, 2020·Antioxidants & Redox Signaling·Zeyu CaiWei Kong
Jan 31, 2021·Genes·Tyler J CreamerElena Gallo MacFarlane
Nov 19, 2020·International Journal of Molecular Sciences·Rui Song, Lubo Zhang
Mar 5, 2021·Science Translational Medicine·Ashraf Ul KabirKyunghee Choi

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Methods Mentioned

BETA
biopsy
electron microscopy
transmission electron microscopy
dissection
enzyme-linked immunosorbent assay
PCR
electrophoresis
affinity purification

Software Mentioned

GraphPad
LabChart
Prism
QCapture Pro
VisualSonics
Clustal Omega
GenScript

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