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.
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