Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2

Kazuyo Yamaji-Kegan, Qingning Su, Daniel J. Angelini, Hunter C. Champion, Roger A. Johns

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


From a mouse model of hypoxia-induced pulmonary hypertension, we previously found a highly upregulated protein in the lung that we named hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 (FIZZ1), and resistin-like molecule α (RELMα). However, the mechanisms of HIMF in the pulmonary vascular remodeling remain unknown. We now demonstrate that HIMF promoted cell proliferation, migration, and the production of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) in pulmonary endothelial cells as well as the production of reactive oxygen species in murine monocyte/macrophage cells. HIMF-induced CD31-positive cell infiltrate in in vivo Matrigel plugs was significantly suppressed by VEGF receptor-2 (VEGFR2) blockade. In ex vivo studies, HIMF stimulated the production of VEGF, MCP-1, and stromal cell-derived factor-1 (SDF-1) in the lung resident cells, and VEGFR2 neutralization significantly suppressed HIMF-induced MCP-1 and SDF-1 production. Furthermore, intravenous injection of HIMF showed marked increase of CD68-positive inflammatory cells in the lungs, and these events were attenuated by VEGFR2 neutralization. Intravenous injection of HIMF also downregulated the expression of VEGFR2 in the lung. These results suggest that HIMF plays critical roles in pulmonary inflammation as well as angiogenesis.

Original languageEnglish (US)
Pages (from-to)L1159-L1168
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number6
StatePublished - Dec 2006


  • Found in inflammatory zone 1
  • Hypoxia-induced mitogenic factor
  • Monocyte chemotactic protein-1
  • Pulmonary inflammation
  • Resistin-like molecule α
  • Vascular endothelial growth factor
  • Vascular endothelial growth factor receptor-2

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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