Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2.
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 alpha (RELMalpha). 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.
Yamaji-Kegan
Kazuyo
K
Department of Anesthesiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Su
Qingning
Q
Angelini
Daniel J
DJ
Champion
Hunter C
HC
Johns
Roger A
RA
D042501:Angiogenic Proteins / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation; D007275:Injections, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000494:pharmacology; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011651:Pulmonary Artery; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
D042501:Angiogenic Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C413576:Retnla protein, mouse; D042461:Vascular Endothelial Growth Factor A; D020932:Nerve Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2