Human hepatic stellate cells secrete adrenomedullin: potential autocrine factor in the regulation of cell contractility

Background/Aims: Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which c an regulate cell contractility in an autocrine manner. It is unknown whethe r human HSCs have receptors for and are able to synthesize the vasodilator peptide adrenomedullin (ADM), a peptide produced by most contractile cells. Methods and results: Stimulation of HSCs with ADM resulted in a dose-depend ent raise in cAMP concentration (radioimmunoassay) and markedly blunted the endothelin-induced increase in [Ca2+](i) and cell contraction, as assessed in cells loaded with fura-2 using a morphometric method. The existence of the receptor CRLR for ADM and their associated proteins RAMP-1 and RAMP-2 w as demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR) . Moreover, activated human HSCs spontaneously secreted ADM in the culture medium in a time-dependent manner. ADM secretion was markedly enhanced by t umour necrosis factor-alpha and interleukin-1 beta. Specific mRNA for ADM ( RT-PCR and Northern blot) was detected in HSCs and increased after incubati on of cells with cytokines. Conclusions: Human HSCs have functional receptors for ADM, the stimulation of which blunts the contractile effect of endothelin-1. Cultured human HSCs secrete ADM in baseline conditions. This secretion is markedly increased b y cytokines. These results suggest that ADM can regulate HSCs' contractilit y in an autocrine manner. (C) 2001 European Association for the Study of th e Liver. Published by Elsevier Science B.V. All rights reserved.