PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression

Ying Yu, Michele Sweeney, Shen Zhang, Oleksandr Platoshyn, Judd Landsberg, Abraham Rothman, Jason X.J. Yuan

Research output: Contribution to journalArticlepeer-review

271 Scopus citations

Abstract

Capacitative Ca2+ entry (CCE) through store-operated Ca2+ (SOC) channels plays an important role in returning Ca2+ to the sarcoplasmic reticulum (SR) and regulating cytosolic free Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt and sufficient Ca2+ in the SR are required for pulmonary artery smooth muscle cell (PASMC) proliferation. We tested the hypothesis that platelet-derived growth factor (PDGF)-mediated PASMC growth involves upregulation of c-Jun and TRPC6, a transient receptor potential cation channel. In rat PASMC, PDGF (10 ng/ml for 0.5-48 h) phosphorylated signal transducer and activator of transcription (STAT3), increased mRNA and protein levels of c-Jun, and stimulated cell proliferation. PDGF treatment also upregulated TRPC6 expression and augmented CCE, elicited by passive depletion of Ca2+ from the SR using cyclopiazonic acid. Furthermore, overexpression of c-Jun stimulated TRPC6 expression and CCE amplitude in PASMC. Downregulation of TRPC6 using an antisense oligonucleotide specifically for human TRPC6 decreased CCE and inhibited PDGF-mediated PASMC proliferation. These results suggest that PDGF-mediated PASMC proliferation is associated with c-Jun/STAT3-induced upregulation of TRPC6 expression. The resultant increase in CCE raises [Ca2+]cyt, facilitates return of Ca2+ to the SR, and enhances PASMC growth.

Original languageEnglish (US)
Pages (from-to)C316-C330
JournalAmerican Journal of Physiology - Cell Physiology
Volume284
Issue number2 53-2
DOIs
StatePublished - Feb 1 2003

Keywords

  • Platelet-derived growth factor
  • Pulmonary hypertension
  • Store-operated cation channels
  • Vascular remodeling

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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