UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Adrenomedullin haploinsufficiency predisposes to secondary lymphedema

Nikitenko, LL; Shimosawa, T; Henderson, S; Mäkinen, T; Shimosawa, H; Qureshi, U; Pedley, RB; ... Boshoff, C; + view all (2013) Adrenomedullin haploinsufficiency predisposes to secondary lymphedema. J Invest Dermatol , 133 (7) 1768 - 1776. 10.1038/jid.2013.47. Green open access

[thumbnail of jid201347a.pdf]
Preview
PDF
jid201347a.pdf

Download (2MB)

Abstract

Secondary lymphedema is a debilitating condition, and genetic factors predisposing to its development remain largely unknown. Adrenomedullin (AM) is peptide encoded, together with proadrenomedullin N-terminal peptide (PAMP), by the Adm gene (adrenomedullin gene). AM and its putative receptor calcitonin receptor-like receptor (CLR) are implicated in angiogenesis and lymphangiogenesis during embryogenesis and wound healing, suggesting their possible involvement in secondary lymphedema. To investigate whether AM deficiency predisposes to secondary lymphedema, we used heterozygous adult mice with Adm gene-knockin stop mutation, which selectively abrogated AM, but preserved PAMP, expression (Adm(AM+/Δ) animals). After hind limb skin incision, Adm messenger RNA expression was upregulated in wounded tissue of both Adm(AM+/+) and Adm(AM+/Δ) mice. However, only Adm(AM+/Δ) animals developed limb swelling and histopathological lymphedematous changes, including epidermal thickening, elevated collagen fiber density, and increased microvessel diameter. Secondary lymphedema was prevented when circulating AM levels in Adm(AM+/Δ) mice were restored by systemic peptide delivery. In human skin, CLR was expressed in tissue components affected by lymphedema, including epidermis, lymphatics, and blood vessels. Our study identified a previously unrecognized role for endogenous AM as a key factor in secondary lymphedema pathogenesis and provided experimental in vivo evidence of an underlying germ-line genetic predisposition to developing this disorder.

Type: Article
Title: Adrenomedullin haploinsufficiency predisposes to secondary lymphedema
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/jid.2013.47
Publisher version: http://dx.doi.org/10.1038/jid.2013.47
Language: English
Additional information: © 2013 The Society for Investigative Dermatology. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/3.0/ PMCID: PMC3682392
Keywords: Adrenomedullin, Animals, Calcitonin Receptor-Like Protein, Cells, Cultured, Endothelium, Lymphatic, Endothelium, Vascular, Gene Knock-In Techniques, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Humans, Lymphedema, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Phenotype, Risk Factors
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/1385553
Downloads since deposit
123Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item