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

J Hepatol. 2001 Feb;34(2):222-9. doi: 10.1016/s0168-8278(00)00016-7.


Background/aims: Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which can regulate cell contractility in an autocrine manner. It is unknown whether 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-dependent 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 was 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 tumour necrosis factor-alpha and interleukin-1beta. Specific mRNA for ADM (RT-PCR and Northern blot) was detected in HSCs and increased after incubation 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 by cytokines. These results suggest that ADM can regulate HSCs' contractility in an autocrine manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin
  • Calcitonin Receptor-Like Protein
  • Calcium Signaling / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Endothelin-1 / pharmacology
  • Humans
  • Interleukin-1 / pharmacology
  • Liver / cytology*
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / physiology
  • Peptides / metabolism*
  • Peptides / pharmacology
  • Receptors, Adrenomedullin
  • Receptors, Calcitonin / metabolism
  • Receptors, Peptide / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • CALCRL protein, human
  • Calcitonin Receptor-Like Protein
  • Endothelin-1
  • Interleukin-1
  • Peptides
  • Receptors, Adrenomedullin
  • Receptors, Calcitonin
  • Receptors, Peptide
  • Tumor Necrosis Factor-alpha
  • Adrenomedullin
  • Cyclic AMP