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INVITED COMMENTARY
The Circuitous Route to Pivotal Mechanisms in Aortic Aneurysm Formation.
Commentary regarding EJVES8677R
Janet T. Powell
*
Vascular Surgery Research Group, Imperial College, London, UK
The earliest research on biological mechanisms associated
with abdominal aortic aneurysm (AAA) focused on the
destruction of the medial connective tissue (mainly collagen
and elastin) and the role of proteases in causing this damage. Numerous other mechanisms including smooth muscle
cell apoptosis, inflammation, angiogenesis, and reactive
oxygen species have been highlighted subsequently. The
research now swings back full circle to again focus on
connective tissue homeostasis in the aorta.
In this issue Chan and colleagues1 show pilot work indicating that the Low-density lipoprotein Receptor-related
Protein 1 (LRP1) is present in greatly reduced amounts in
the media and adventitia of AAAs. This type of work is
becoming increasingly difficult to do, since the availability of
aneurysm sac biopsies at open repair is becoming scarce as
endovascular repair becomes the preferred corrective procedure. Why focus on a protein with a name unrelated to
connective tissue or proteases? The name LRP1 reflects the
structure of the protein not its function, since it functions as
a receptor for several proteases and proteaseeantiprotease
complexes and is found in vascular smooth muscle cells and
macrophages. The LRP1 gene was identified in genomewide association studies (genome scanning of thousands
of patients with AAA compared with thousands of persons
without AAA) as being strongly associated with AAA.2 Such
studies offer a minimally biased approach to identifying
proteins involved in the mechanisms of disease. Initially
LRP1 was a surprise finding.
How do such findings get taken forward? Perhaps unsurprisingly, deletion of the LRP1 gene from vascular
smooth muscle cells in mice resulted in aortic aneurysm,3
but similar findings have been observed with deletion of
DOI of original articles: http://dx.doi.org/10.1016/j.ejvs.2013.08.006
* J.T. Powell, Vascular Surgery Research Group, Imperial College, London,
UK.
E-mail address: [email protected] (J.T. Powell).
1078-5884/$ e see front matter Ó 2013 European Society for Vascular
Surgery. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejvs.2013.08.007
a wide variety of other genes. Very recently, more detailed
studies in mice have shown that LRP1 protects the aorta
(and other arteries) from degenerative changes by regulating both protease activity and the deposition of connective tissue.4 This implies that a relative lack of LRP1
could result in both increased protease activity and
impaired regeneration of damaged connective tissue. Full
circle complete in mice.
Chan et al.1 have taken the first step in supporting similar
control of proteolysis and connective tissue homeostasis by
LRP1 in the diseased human aorta. This offers renewed
hope for identification a biological pathway specific to the
development of aneurysms. Targeting such a pathway may
permit the development of aneurysm-specific therapies in
the future.
REFERENCES
1 Chan CYT, Chan YC, Cheuk BL, Cheng SW. A pilot study on low
density lipoprotein receptor related protein 1 in Chinese patients with abdominal aortic aneurysm. Eur J Vasc Endovasc
Surg 2013;46:549e56.
2 Bown MJ, Jones GT, Harrison SC, Wright BJ, Bumpstead S,
Baas AF, et al. Abdominal aortic aneurysm is associated with a
variant in low-density lipoprotein receptor-related protein 1. Am
J Hum Genet 2011;89:619e27.
3 Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J. LRP: role in
vascular wall integrity and protection from atherosclerosis. Science 2003;300:329e32.
4 Muratoglu SC, Belgrave S, Hampton B, Migliorini M,
Coksaygan T, Chen L, et al. LRP1 protects the vasculature by
regulating levels of connective tissue growth factor and HtrA1.
Arterioscler Thromb Vasc Biol 2013;33:2137e46.