Keywords: adrenomedullin signaling in lymphatic endothelial cells
Adrenomedullin and its receptors are highly expressed in endothelial cells and are required for the normal development of the cardiovascular system, including the heart, lymphatic vessels and placenta. Using a variety of gene targeted animal models we have characterized a novel role for adrenomedullin and its receptors in the development and function of these cardiovascular organs. A major emphasis area of our laboratory is to define the function of adrenomedullin signaling in lymphatic endothelial cells. Mice with targeted null mutations in AM, or its receptor components CLR and RAMP2 die at mid-gestation with hydrops fetalis associated with proliferative defects in the growth and development of the lymphatic vascular system—a discovery that identifies the first, pharmacologically-tractable GPCR system involved in developmental lymphangiogenesis. Recently, we have also discovered that loss of AM signaling in adult mice recapitulates numerous pathophysiological sequelae associated with human lymphangiectasia. Expression of CLR and RAMP2 is potently up-regulated in lymphatic endothelial cells and stimulation of these receptors by AM can regulate both their permeability and proliferation. Most recently, we have discovered a novel function for the atypical chemokine decoy receptor, CXCR7, in controlling the bioavailability of AM during embryonic development. Since AM and its receptors represent one of the few pharmacologically tractable factors for lymphatic endothelial cells, AM-based therapies may eventually become useful for the treatment of lymphatic-based conditions such as lymphedema or lymphatic tumor metastasis. To this end, we are actively working with the pharmaceutical industry toward small molecule compound screens and peptide-based approaches for the therapeutic modulation of AM signaling in a variety of cardiovascular-related disorders.