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.
![[thumbnail of jid201347a.pdf]](https://discovery.ucl.ac.uk/style/images/fileicons/application_pdf.png) 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 |
Archive Staff Only
 |
View Item |
