Hypoxia is an inducer of vasodilator agents in peritoneal macrophages of cirrhotic patients

Authors

  • Pilar Cejudo-Martín,

    1. Hormonal Laboratory, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Manuel Morales-Ruiz,

    1. Hormonal Laboratory, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Josefa Ros,

    1. Hormonal Laboratory, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Miguel Navasa,

    1. Liver Unit, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Guillermo Fernández-Varo,

    1. Hormonal Laboratory, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Josep Fuster,

    1. Hepatic Surgery Department, 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, Barcelona, Spain
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  • Francisca Rivera,

    1. Hormonal Laboratory, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Vicente Arroyo,

    1. Liver Unit, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Juan Rodés,

    1. Liver Unit, Hepatic Surgery Department, 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, Barcelona, Spain
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  • Wladimiro Jiménez

    Corresponding author
    1. Hormonal Laboratory, Hepatic Surgery Department, 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, Barcelona, Spain
    • Laboratorio Hormonal, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain. fax: (34) 93-4515272.
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Abstract

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% O2) or normoxic conditions (21% O2). 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-1α and HIF-1β messengers and HIF-1β protein subunit remained unchanged regardless of O2 tension, whereas HIF-1α 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 O2 tension could enhance the synthesis of macrophage-derived vasodilators, thus aggravating the circulatory disturbance of these patients.

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