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Centre of Molecular Endocrinology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University, London, UK
¹ Centre for Biochemical Pharmacology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University, London, UK
² Research Centre for Clinical and Diagnostic Oral Sciences, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University, London, UK

(Requests for offprints should be addressed to N Schwarz; Email: n.schwarz{at}qmul.ac.uk)

Adrenomedullin (AM) is a multifunctional peptide hormone, which plays a significant role in vasodilation and angiogenesis, implicating it in hypertension as well as in carcinogenesis. AM exerts its effects via the calcitonin receptor-like receptor (CRLR, now known as CL) complexed with either receptor activity modifying protein (RAMP) 2 or 3. We have investigated the effect of AM on immortalized human microvascular endothelial cells 1, since endothelial cells are a major source as well as a target of AM actions in vivo. Cells treated with AM showed elevated cAMP in a time (5–45 min)-dependent and dose (10^–6–10^–14 M)-dependent manner. Pre-treatment with the AM receptor antagonist AM_22–52 partially suppressed the AM-induced increase in cAMP levels. An increase in extracellular signal-regulated kinase 1/2 phosphorylation was observed after 5 min of treatment with 10^–8 M AM. This phosphorylation was specific, since we were able to block the AM-induced effect with 1 µM U0126, a specific mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Using real-time PCR, we were able to show for the first time that AM upregulates peptide and mRNA expression of vascular endothelial growth factor (VEGF). However, AM treatment of cells did not result in increased cell proliferation. Instead, we observed that AM and VEGF induced cell migration, which could be inhibited by the AM_22–52 and anti-VEGF antibody respectively. AM also significantly elevated mRNA levels of CL (after 2 and 24 h treatment) and RAMP2 (after 1 and 24 h treatment). The upregulation of the AM receptor at two time points reflects possibly different cellular responses to short- and long-term exposure to AM.

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