The recent discovery of an essential hormone in the proper development the lymph system in mice may have far reaching implications for either the prevention of or treatment of lymphedema in humans according to new studies released this previous week.
As research continues, I will update our information.
The Endocrine Society
Joy Patricia Hinson, Supriya Kapas and David Michael Smith Department of Molecular and Cellular Biology (J.P.H.) and Clinical Sciences Research Centre (S.K.), St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, London E1 4NS; and Department of Metabolic Medicine (D.M.S.), Division of Investigative Sciences, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN United Kingdom
Since the discovery of adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing adrenomedullin far exceeding those that do not. In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting adrenomedullin and of the mechanisms regulating gene expression. The data on circulating adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative adrenomedullin receptor clones and signal transduction pathways are described. In Section IV the various actions of adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered. Finally, in Section V, we consider some unresolved issues and propose future areas for research
AM was initially identified as a vasodilator, some have cited this as the most potent endogenous vasodilatory peptide found in the body (Cockcroft et al., 1997). Differences in opinion regarding the ability of AM to relax vascular tone arises from the differences in the model system used (Hamid and Baxter, 2005). Other effects of AM include increasing the tolerance of cells to oxidative stress and hypoxic injury and angiogenesis. AM is seen as a positive influence in diseases such as hypertension, myocardial infarction, chronic obstructive pulmonary disease and other cardiovascular diseases, whereas it can be seen as a negative factor in potentiating the potential of cancerous cells to extend their blood supply and cause cell proliferation.
Dec 21, 2007
ScienceDaily (Dec. 21, 2007) – The two vascular systems in mammals develop sequentially during embryonic life. The blood vascular system, which is essential for the delivery of oxygen and nutrients to the tissues, develops first. This is followed by the lymphatic vascular system that returns extracellular fluid and proteins back to the blood vascular system from the spaces between the tissues.
New data reported in two studies in the Journal of Clinical Investigation has identified signaling by a peptide known as AM in the development of both the blood and lymphatic vascular systems in mice. How the two groups observe similar mouse phenotypes but one concludes they are due to lymphatic vascular system defects and the other to blood vascular defects is discussed in an accompanying commentary by Mark Kahn from the University of Pennsylvania, Philadelphia.
Kathleen Caron and colleagues at the University of North Carolina, Chapel Hill, showed that mice lacking AM or either one of the two components of its receptor (Calcrl and RAMP2) died mid-gestation after developing interstitial lymphedema without hemorrhage. Detailed analysis indicated a defect in these mice in lymphatic vascular development, and in vitro experiments demonstrated that AM signaling through Calcrl/RAMP2 drives the proliferation of lymphatic endothelial cells.
The authors therefore suggested, “that lack of lymphatic proliferative signals during lymphangiogenesis results in smaller, lower-capacity jugular lymphatic vessels that are unable to accommodate the normal uptake of extravasated fluid and thus exacerbates massive interstitial edema.”
Similarly, Takayuki Shindo and colleagues from the Shinshu University Graduate School of Medicine, Japan, established that mice lacking RAMP2 died mid-gestation due to severe edema and hemorrhage. However, they observed that the arterial walls of these mice were abnormally thin and their typical structure was severely disrupted.
Furthermore, overexpression of RAMP2 in endothelial cells enhanced their ability to form blood capillaries in vitro. The authors therefore concluded that, “RAMP2 is a key determinant of the effects of AM on the vasculature and is essential for angiogenesis and vascular integrity in mice.”
Article: Adrenomedullin signaling is necessary for murine lymphatic vascular development. Journal of Clinical Investigation. December 20, 2007.
Adapted from materials provided by Journal of Clinical Investigation.
THURSDAY, Dec. 20 (HealthDay News) – A hormone called adrenomedullin may prove an effective drug target for treating lymphedema, a painful swelling of the limbs that can follow breast cancer or other cancer treatment, U.S. researchers say.
It may also help prevent the spread of cancer, according to a team from the University of North Carolina at Chapel Hill School of Medicine.
Adrenomedullin, which is secreted by cells throughout the body, is known to play a role in cardiovascular disease and other cell functions. In a new study, the UNC group found that adrenomedullin also plays an important role in the formation of the lymphatic system in mice.
They said it may be possible to develop drugs that target this hormone in order to help the more than 100 million people worldwide who suffer from lymphedema. The condition occurs when the lymphatic system fails to work properly. In rare cases, it is genetic, but millions suffer lymphedema due to parasitic infections or as the aftermath of cancer therapies.
Currently, the only treatments for lymphedema include massage and the use of low-compression stockings and other garments. But these aren't much help, the UNC researchers said.
“Our research also may lead to therapies to prevent cancer cells from traveling through these lymphatic vessels to infiltrate other parts of the body,” senior study author Kathleen M. Caron, assistant professor of cell and molecular physiology and genetics, said in a prepared statement.
By Rafael_B Published Dec 26, 2007
A new drug target for preventing lymphedema disease has been discovered by a team of researchers, according to a new study published recently in the prestigious medical Journal of Clinical Investigation.
The study has established that a previously known hormone secreted by all body cells and related to cardiovascular disease, may be critical in the development of the lymphedema cancer disease. The idea is, according to the new study, to target this hormone, called adrenomedullin.
The lymphedema cancer disease is a potentially severe disease that causes painful swelling in arms and legs. Experts estimate that the lymphedema disease affects more than 1000 million people worldwide.
Kathleen M. Caron, PhD., from the Department of Cell and Molecular Physiology and The Department of Genetics, The University of North Carolina, Chapel Hill, NC. (USA), led the study along with colleagues from both departments at UNC. They believe, according to the study, that have discovered the basis for therapies that will prevent cancer cells to travel through the lymph system preventing then the spreading of the cancer to other parts of the human body.
The hormone Adrenomedullin is involved in a variety of human body functions. For example it is responsible for regulating blood vessel opening and promote the growth of new blood vessels. It helps control metabolism, antibacterial issues and nerve signaling.
Caron and colleagues have discovered a new function for adrenomodullin. This small peptide is related to the normal development of the lymphatic system, which is an relevant part of the human body's immune system.
The lymphatic system is formed by a myriad of tiny-networked tubes and nodes that transport a fluid called lymph. These tubes resemble blood vessels and run throughout the human body. Its function is catch up immune cells that have leach out from cells and get them back were they belong.
Caron and her team of colleagues took mice and genetically manipulated until they lacked completely of adrenomodullin. In these mice the developed lymphangiogenesis, that is the swelling on the lymph nodes, known to cause lymphedema.
The only treatment available today for lymphedema is to using low-compression stockings and garments, and massage. But these are not of too much help.
In this new study researchers have described three new targets, adrenomedullin and two of its partners in the cell, which could offer hope for lymphedema sufferers since they could be the basis for the pharmaceutical treatment for lymphedema.
The authors believe that by increasing adrenomedullin, the lymph sacs will proliferate and take up more fluid. This could be the basis for a new treatment for lymphedema and also be helpful preventing the spread of cancer since cancers spreads sometimes through the lymphatic system
Caron et al. . 2007. Adrenomedullin signaling is necessary for murine lymphatic vascular development. J. Clin. Invest. doi:10.1172/JCI33302