We have pioneered the study of G protein-coupled receptor (GPCR) pathways, including adrenomedullin signaling, in the development and function of the lymphatic vascular system. Lymphatics play essential roles in maintaining appropriate interstitial fluid balance, trafficking of immune cells and absorption of fat with the gastrointestinal tract. A major emphasis area of our laboratory is to explore the normal and pathological functions of lymphatic vessels in peripheral organs such as the gastrointestinal tract, heart, skin and eye. 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. We have also discovered that loss of AM signaling in adult mice recapitulates numerous pathophysiological sequelae associated with human lymphangiectasia. 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. Our most recent work using spatiotemporal gene engineering approaches permits us to compare and contrast the differences in lymphatic development and function in a variety of peripheral organs, like the gastrointestinal tract and heart—an area of broad and comparative investigation that has been largely understudied in the field to date.
- Fritz-Six K, Dunworth W, Li M, Caron KM. Adrenomedullin Signaling is Necessary for Murine Lymphatic Vascular Development. J Clin Invest. 2008 Jan. 118:40-50.
- Dunworth W & Caron KM. G protein-coupled receptors as potential drug targets for lymphangiogenesis and lymphatic vascular diseases. Arterioscler Thromb Vascul Biol. 2009 May. 29(5):650-6.
- Hoopes SL, Willcockson HH, Caron KM. Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. PLoS One. 2012 Sep 7(9):e45261.
- Karpinich NO, Kechele DO, Espenschied ST, Willcockson HH, Caron KM 2012 Dosage of adrenomedullin correlates with tumor lymphangiogenesis and distant metastasis. FASEB J. 2013 Feb. 27(2):590-600
- Klein KR and Caron KM 2015 Adrenomedullin in lymphangiogenesis: from development to disease. Cell Mol Life Sci. 2015 Aug; 72(16):3115-26.
- Karpinich NO and Caron KM. Gap junction coupling is required for tumor cell migration through lymphatic endothelium. Arterioscler Thromb Vasc Biol. 2015 May;35(5):1147-55