Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease

Allan Lawrie, Edda Spiekerkoetter, Eliana C. Martinez, Noona Ambartsumian, W. John Sheward, Margaret R. MacLean, Anthony J. Harmar, Ann Marie Schmidt, Eugene Lukanidin, Mailene Rabinovitch

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


Heightened expression of the S100 calcium-binding protein, S100A4/Mts1, is observed in pulmonary vascular disease. Loss of serotonin (5-hydroxytryptamine [5-HT]) receptors or of the serotonin transporter (SERT) attenuates pulmonary hypertension in animals, and polymorphisms causing gain of SERT function are linked to clinical pulmonary vascular disease. Because 5-HT induces release of S100β, we investigated the codependence of 5-HT receptors and SERT in regulating S100A4/Mts1 in human pulmonary artery smooth muscle cells (hPA-SMC). 5-HT elevated S100A4/Mts1 mRNA levels and increased S100A4/Mts1 protein in hPA-SMC lysates and culture media. S100A4/Mts1 in the culture media stimulated proliferation and migration of hPA-SMC in a manner dependent on the receptor for advanced glycation end products. Treatment with SB224289 (selective antagonist of 5-HT1B), fluoxetine (SERT inhibitor), SERT RNA-interference, and iproniazid (monoamine oxidase-A inhibitor), blocked 5-HT-induced S100A4/Mts1. 5-HT signaling mediated phosphorylation (p) of extracellular signal-regulated kinase 1/2 (pERK1/2), but pERK1/2 nuclear translocation depended on SERT, monoamine oxidase activity, and reactive oxygen species. Nuclear translocation of pERK1/2 was required for pGATA-4-mediated transcription of S100A4/Mts1. These data provide evidence for a mechanistic link between the 5-HT pathway and S100A4/Mts1 in pulmonary hypertension and explain how the 5-HT1B receptor and SERT are codependent in regulating S100A4/Mts1.

Original languageEnglish (US)
Pages (from-to)227-235
Number of pages9
JournalCirculation research
Issue number3
StatePublished - Aug 5 2005
Externally publishedYes


  • ERK1/2
  • Pulmonary hypertension
  • S100A4/Mts1
  • Serotonin
  • Smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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