Hypoxia is an inducer of vasodilator agents in peritoneal macrophages of cirrhotic patients.
The aim of the investigation was to assess whether hypoxia induces the production of endogenous vasoactive peptides in macrophages of cirrhotic patients with ascites because low tissue oxygenation is a relatively frequent event in these patients. Peritoneal macrophages were isolated from ascites, seeded on well plates, and cultured at different times under hypoxic (5% O(2)) or normoxic conditions (21% O(2)). Then, accumulation of vasoactive peptides sensitive to hypoxia including endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and adrenomedullin (ADM) was measured. Only VEGF and ADM were constitutively secreted, and hypoxia further stimulated the release of these vasodilator peptides. In concordance, increased messenger RNA (mRNA) levels of VEGF and ADM were found at culturing macrophages in hypoxia. This characteristic response was not observed in circulating monocytes of either cirrhotic patients or healthy subjects. Next the expression of the transcription factor, hypoxia inducible factor 1 (HIF-1), was analyzed. Expression of HIF-1alpha and HIF-1beta messengers and HIF-1beta protein subunit remained unchanged regardless of O(2) tension, whereas HIF-1alpha protein subunit was overexpressed under hypoxic conditions. Moreover, conditioned medium from macrophages cultured under hypoxic conditions promoted a larger nitric oxide (NO) release in endothelial cells than that of normoxic macrophages. In conclusion, these data indicate that hypoxia induces the synthesis of VEGF and ADM in macrophages of cirrhotic patients, likely through HIF-1-enhanced transcriptional activity. These data suggest that a local reduction in O(2) tension could enhance the synthesis of macrophage-derived vasodilators, thus aggravating the circulatory disturbance of these patients.
Cejudo-Martín
Pilar
P
Hormonal Laboratory, Liver Unit, Institut de Malalties Digestives, Hospital Clínic Universitari and Institut d'Investigacions Biomèdiques August Pi i Sunyer and Instituto Reina Sofia de Investigaciones Nefrológicas, University of Barcelona, Spain.
Morales-Ruiz
Manuel
M
Ros
Josefa
J
Navasa
Miguel
M
Fernández-Varo
Guillermo
G
Fuster
Josep
J
Rivera
Francisca
F
Arroyo
Vicente
V
Rodés
Juan
J
Jiménez
Wladimiro
W
D053607:Adrenomedullin; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000502:physiology*
D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010455:Peptides; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D053607:Adrenomedullin; D009569:Nitric Oxide; D010100:Oxygen