Hypoxia-Inducible Angiopoietin-2 Expression Is Mimicked by Iodonium Compounds and Occurs in the Rat Brain and Skin in Response to Systemic Hypoxia and Tissue Ischemia

Angiopoietins are ligands for the endothelial cell tyrosine kinase receptor Tie-2. Ang-1, the major physiological activator of Tie-2, promotes blood vessel maturation and stability. Ang-2 counteracts this effect by competitively inhibiting the binding of Ang-1 to Tie-2. Using a combined RNase protec...

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Vydané v:The American journal of pathology Ročník 156; číslo 6; s. 2077 - 2089
Hlavní autori: Mandriota, Stefano J., Pyke, Charles, Di Sanza, Corinne, Quinodoz, Pierre, Pittet, Brigitte, Pepper, Michael S.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 01.06.2000
ASIP
American Society for Investigative Pathology
Predmet:
Angiopoietin-2
Animals
Biphenyl Compounds - pharmacology
Brain - metabolism
Cattle
Cell Line
Endothelial Growth Factors - metabolism
Humans
Hypoxia - metabolism
Ischemia - metabolism
Lymphokines - metabolism
Male
Onium Compounds - pharmacology
Proteins - metabolism
Rats
Rats, Sprague-Dawley
Rats, Wistar
Regular
RNA, Messenger - metabolism
Skin - blood supply
Skin - metabolism
Up-Regulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
ISSN:0002-9440, 1525-2191
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Shrnutí:Angiopoietins are ligands for the endothelial cell tyrosine kinase receptor Tie-2. Ang-1, the major physiological activator of Tie-2, promotes blood vessel maturation and stability. Ang-2 counteracts this effect by competitively inhibiting the binding of Ang-1 to Tie-2. Using a combined RNase protection/semiquantitative reverse transcriptase-polymerase chain reaction approach, we demonstrate that hypoxia up-regulates Ang-2 mRNA levels by up to 3.3-fold in two human endothelial cell lines. In bovine microvascular endothelial (BME) cells, the flavoprotein oxidoreductase inhibitor diphenylene iodonium (DPI) and the related compound iodonium diphenyl mimic induction of Ang-2 but not vascular endothelial growth factor (VEGF) by hypoxia; in combination with hypoxia, DPI further increases Ang-2 expression but has no effect on the induction of VEGF by hypoxia. Neither Ang-2 or VEGF was increased by cyanide or rotenone, suggesting that failure in mitochondrial electron transport is not involved in the oxygen-sensing system that controls their expression. In ischemic rat dorsal skin flaps or in the brain of rats maintained for 12 hours under conditions of hypoxia, Ang-2 mRNA was up-regulated 7.5- or 17.6- fold, respectively. VEGF was concomitantly increased, whereas expression of Ang-1, Tie-2, and the related receptor Tie-1 was unaltered. In situ hybridization localized Ang-2 mRNA to endothelial cells in hypoxic skin. These findings 1) show that up-regulation of Ang-2 by hypoxia occurs widely in endothelial cells in vitro and in vivo; 2) suggest that induction of Ang-2, but not VEGF, by hypoxia in BME cells is controlled by a flavoprotein oxidoreductase that is sensitive to iodonium compounds; and 3) point to Ang-2 and VEGF as independently regulated and selective effectors of hypoxia-induced vascular sprouting.
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ISSN:0002-9440
1525-2191
DOI:10.1016/S0002-9440(10)65079-1