Article

Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats

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Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.

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Acknowledgements

W.J.K. and S.M.F. received funding from the Fund for Scientific Research (FWO) Flanders (11J9513N, 1802154N).

Disclaimer

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Van der Graaff Denise and Kwanten Wilhelmus J contributed equally to this work.

Affiliations

  1. Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium

    • Denise Van der Graaff
    • , Wilhelmus J Kwanten
    • , Wim Verlinden
    • , Peter P Michielsen
    •  & Sven M Francque
  2. Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    • Denise Van der Graaff
    • , Wilhelmus J Kwanten
    • , Filip J Couturier
    • , Jesse S Govaerts
    • , Wim Verlinden
    • , Isabel Brosius
    • , Michiel D’Hondt
    • , Benedicte Y De Winter
    • , Joris G De Man
    • , Peter P Michielsen
    •  & Sven M Francque
  3. Department of Pathology, Antwerp University Hospital, Laboratory of Pathology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    • Ann Driessen

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Sven M Francque.

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