Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1

Aarti Raghavan, Guofei Zhou, Qiyuan Zhou, Joyce Christina F. Ibe, Ramaswamy Ramchandran, Qiwei Yang, Harini Racherla, Pradip Raychaudhuri, J. Usha Raj

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. Here, we report for the first time, to the best of our knowledge, a novel function of FoxM1 in the hypoxia-stimulated proliferation of human pulmonary artery smooth muscle cells (HPASMCs). Exposure to hypoxia caused a marked up-regulation of FoxM1 gene expression, mainly at the transcription level, and this induction correlated with HPASMC cell proliferation. The knockdown of FoxM1 inhibited the hypoxiastimulated proliferation of HPASMCs.Wefound that the knockdown of HIF-2α, but not HIF-1α, diminished FoxM1 induction in response to hypoxia. However, the knockdown of FoxM1 did not alter expression levels of HIF-2α or HIF-1α, suggesting that HIF-2α is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2α-dependent pathway, thereby promoting HPASMC proliferation.

Original languageEnglish (US)
Pages (from-to)431-436
Number of pages6
JournalAmerican journal of respiratory cell and molecular biology
Issue number4
StatePublished - Apr 2012
Externally publishedYes


  • Cell proliferation
  • FoxM1
  • HIF
  • Hypoxia
  • Pulmonary artery smooth muscle cells

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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