Characterisation of the pulmonary vascular response to hypoxia in mitochondrial uncoupling protein 2 deficient mice

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HoeresTimm_2013_12_11.pdf (2.77 MB)

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2013

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DOI:
http://dx.doi.org/10.22029/jlupub-13878

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is a specific physiological reaction of the pulmonary circulation which optimizes pulmonary gas exchange. Due to selective vaso-constriction of precapillary pulmonary vessels, systemic oxygen availability is pre-served in case of a localized reduction of ventilation or a lack of local alveolar oxygen. Additional interdependent mechanisms lead to vascular remodelling during adaptation to chronic hypoxia. Similar changes are also part of the pathogenesis of certain severe pulmonary vascular diseases. Despite intensive research, the sub-cellular and molecular nature of the mechanisms enabling HPV and vascular remodelling due to hypoxia re-main unclear. Uncoupling protein 2 (UCP-2) is a mitochondrial protein and a more re-cently identified homologue of the protein thermogenin (UCP-1). Recent studies sug-gest important interaction between UCP-2 and the signalling pathways of HPV. Against this background, the aim of this study was to investigate the role of UCP-2 in the lungs´ adaptation to acute, sustained and chronic hypoxia. Therefore important char-acteristics of HPV in wild-type (WT) and UCP-2 deficient (UCP-2 -/- ) mice were com-pared. It could be demonstrated that while acute HPV was enhanced in UCP-2 -/- mice, sustained HPV was attenuated. This difference was found to be specific for hypoxia as a vasoconstrictor stimulus. The muscularization of pulmonary vessels was increased un-der normoxic conditions in UCP-2 -/- mice and following exposure to chronic hypoxia the right ventricular systolic pressure was found elevated in UCP-2 -/- mice compared to WT mice. The results depict that ablation of UCP-2 divergently impacts the consecutive phases of HPV by a yet incompletely understood mechanism. This requires differences in the sen-sor or mediator systems of acute and sustained HPV. UCP-2 is able to directly or indi-rectly control the muscularization of pulmonary vessels under normoxic conditions and likely the pulmonary vascular tone under chronic hypoxia.

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