Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia

Circulation. 2006 Apr 18;113(15):1857-64. doi: 10.1161/CIRCULATIONAHA.105.591321. Epub 2006 Apr 10.


Background: The mechanism of pulmonary artery smooth muscle cell (PA-SMC) hyperplasia in idiopathic pulmonary artery hypertension (iPH) may involve both an inherent characteristic of PA-SMCs and abnormal control by external stimuli. We investigated the role of pulmonary microvascular endothelial cells (P-ECs) in controlling PA-SMC growth.

Methods and results: Serum-free medium of quiescent P-ECs elicited marked PA-SMC proliferation, and this effect was greater with P-ECs from patients with iPH than from control subjects and greater with PA-SMCs from these patients than from control subjects. Fluoxetine, which inhibits serotonin-induced mitogenesis by blocking the serotonin transporter, and p-chlorophenylalanine, which inhibits serotonin synthesis by blocking tryptophan hydroxylase (TPH), caused a similar 60% reduction in the growth-promoting effect of P-EC media, whereas endothelin receptor blockers had no effect. Assays of TPH activity in P-EC medium based on p-chlorophenylalanine-sensitive 5-hydroxytryptophan accumulation or serotonin determination indicated serotonin synthesis by P-ECs and an increase in this TPH-dependent process in iPH. Expression of the tph1 gene encoding the peripheral form of the TPH enzyme was increased in lungs and P-ECs from patients with iPH. Lung TPH1 immunostaining was confined to the pulmonary vessel intima.

Conclusions: P-ECs produce paracrine factors governing PA-SMC growth. Serotonin, the main P-EC-derived growth factor, is overproduced in iPH and contributes to PA-SMC hyperplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Cell Division / drug effects
  • Cells, Cultured
  • Culture Media, Serum-Free / chemistry
  • Culture Media, Serum-Free / pharmacology
  • Endothelial Cells / metabolism*
  • Female
  • Humans
  • Hyperplasia
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Lung / enzymology
  • Lung / metabolism
  • Male
  • Middle Aged
  • Muscle, Smooth / pathology*
  • Myocytes, Smooth Muscle / pathology*
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Serotonin / analysis
  • Serotonin / biosynthesis
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Tryptophan Hydroxylase / metabolism


  • Culture Media, Serum-Free
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Tryptophan Hydroxylase