# Vascular Extracellular Matrix in Arterial Development and Disease

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2020 · $153,352

## Abstract

PROJECT SUMMARY
Elastin, the major component of vascular extracellular matrix, provides arteries the elastic recoil
necessary for normal heart function. Both human genetics and animal studies have identified
several extracellular matrix proteins as important for proper elastic fiber formation, however the
process by which elastin assembles into a functional fiber remains unclear. In addition to
elastin, two proteins required in this regard are lysyl oxidase (LOX) and Fibulin-4 (FBLN4),
which will be the focus of this proposal. Mice deficient in Fbln4 die shortly after birth due to
cardiopulmonary failure from the absence of intact elastic fibers. Recently humans with a
multisystem disorder known as autosomal recessive cutis laxa type 1B (ARCL 1B) were
identified to carry mutations in FBLN4. Patients with ARCL1B develop inelastic skin, aortic
aneurysms, arterial tortuosity, pulmonary emphysema and skeletal abnormalities. Using a
mouse model harboring a Fbln4 mutation (E57K) seen in humans, our preliminary studies
showed significant elastic fiber fragmentation and wall disarray in large arteries, ascending
aortic aneurysms, arterial stiffness and hypertension in Fbln4E57K mice. Surprisingly however,
elastic fibers in resistance arteries were unaffected, suggesting the process of elastic fiber
formation, which was previously thought to be the same in all tissues, may differ between elastic
and muscular arteries. The studies proposed herein will address the role FBLN4 plays in
maintaining arterial wall integrity and the mechanisms by which its disruption leads to
aneurysmal disease. The specific aims are to: (1) Define the functional interaction between
FBLN4 and LOX and determine how mutations in FBLN4 lead to abnormal elastic fiber
formation and vessel wall weakness; (2) Identify mechanism(s) underlying differences in elastic
fiber assembly and arterial wall integrity between Fbln4E57K elastic and muscular arteries; and (3)
Investigate alterations in signaling pathways and blood pressure as potential therapeutic targets
for aneurysm formation in Fbln4E57K mice. Addressing these aims will not only enhance our
understanding of the role of FBLN4 in vessel wall maturation, but will also identify potential
therapeutic targets for aneurysmal disease.

## Key facts

- **NIH application ID:** 9949426
- **Project number:** 5K08HL135400-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Carmen M. Halabi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,352
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949426

## Citation

> US National Institutes of Health, RePORTER application 9949426, Vascular Extracellular Matrix in Arterial Development and Disease (5K08HL135400-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9949426. Licensed CC0.

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