The highly conserved peptide, adrenomedullin (Adm=gene; AM=peptide), is known to play a role in the development and permeability of the lymphatic vascular system. AM signals through a G-Protein coupled receptor, calcitonin receptor-like receptor (Calcrl), associated with a receptor activity modifying protein (Ramp2/3). To determine the role of AM signaling during adulthood, several studies were undertaken using mice with temporal deletion of Calcrl and mice haplo-insufficient for Adm. Temporal loss of Calcrl in adult mice resulted in multi-organ lymphangiectasia associated with increased lymphatic permeability and disrupted lymphatic function. These mice also exhibited reduced body weight due to impaired lipid absorption and protein-losing enteropathy. Therefore, AM signaling is required for preservation of normal lymphatic function and permeability. An ear wound assay was performed on mice haplo-insufficient for Adm to stimulate lymphangiogenesis as well as angiogenesis. Genetic reduction of Adm impaired lymphangiogenesis in response to the wound, but angiogenesis was unaffected. AM is highly expressed in all endothelial cells, but from these studies as well as previous developmental studies we have found that there is an enhanced response to AM signaling in lymphatic endothelial cells that is imparted by increased levels of receptor expression. To further understand the molecular differences between lymphatic and blood endothelial cells that could contribute to the different responses to AM signaling, we explored the expression and function of the serum binding protein for AM, complement factor H. Previous studies showed that AM activity is enhanced by complement factor H and previous microarray data revealed that the complement factor H gene is upregulated in lymphatic endothelial cells. Here we show that complement factor H protein expression is increased in lymphatic endothelial cells and it enhances the AM-induced migration response to a scratch assay in lymphatic endothelial cells. Overall, results from these studies established the importance of AM signaling in lymphatic vessels during adulthood and identified a factor contributing to the different responses to AM in lymphatic and blood endothelial cells.