Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction

  • Swenja Kröller-Schön
  • Thomas Jansen
  • Thi Lan P. Tran
  • Miroslawa Kvandová
  • Sanela Kalinovic
  • Matthias Oelze
  • John F. KeaneyJr.
  • Marc Foretz
  • Benoit Viollet
  • Andreas Daiber
  • Sabine Kossmann
  • Jeremy Lagrange
  • Katie Frenis
  • Philip Wenzel
  • Thomas Münzel
  • Eberhard SchulzEmail author
Original Contribution


Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress. However, the underlying mechanisms are incompletely understood and may involve endothelial NOX-2 upregulation or facilitated vascular infiltration of phagocytic cells. Therefore, the current study was designed to investigate the vascular effects of chronic angiotensin II (AngII) infusion in mice with an endothelial-specific α1AMPK deletion. A mouse strain with endothelial-specific α1AMPK deletion was generated by breeding α1AMPKflox/flox mice with TekCre+ or Cadh5Cre+ mice. Chronic AngII infusion (0.5 mg/kg/day for 7day) caused mild endothelial dysfunction in wild-type mice that was significantly aggravated in endothelial α1AMPK knockout mice. Aortic NOX-2 and CD68 expression were increased, indicating that infiltrating leukocytes may significantly contribute to enhanced vascular oxidative stress. Flow cytometry revealed a higher abundance of aortic CD90.2+ T-cells, CD11b+F4/80+ macrophages and Ly6GLy6C+ monocytes. Vascular mRNA expression of monocyte chemoattractant protein 1, CCL5 and vascular cell adhesion molecule 1 was enhanced in AngII-infused mice lacking endothelial α1AMPK, facilitating the recruitment of inflammatory cells to the vessel wall. In addition, AngII-induced upregulation of cytoprotective heme oxygenase 1 (HO-1) was blunted in mice with endothelial α1AMPK deletion, compatible with an impaired antioxidant defense in these animals. In summary, endothelial expressed α1AMPK limits the recruitment of inflammatory cells to the vessel wall and maintains HO-1 mediated antioxidant defense. Both mechanisms reduce vascular oxidative damage and preserve endothelial function during chronic AngII treatment.


α1AMPK Macrophages Vascular inflammation Reactive oxygen species Endothelial dysfunction 





Adenosine monophosphate


AMP-activated protein kinase


Angiotensin II


C–C chemokine receptor type 2


CC-chemokine ligand 5




Endothelial nitric oxide synthase


Glycerol trinitrate


Heme oxygenase 1


Nicotinamide adenine dinucleotide phosphate, reduced form


Monocyte chemotactic protein 1


Nitric oxide


Reactive oxygen species


Polyethylene-glycolated-superoxide dismutase


TATA box binding protein


Vascular cell adhesion protein 1



We thank Bettina Mros, Angelica Karpi, Jessica Rudolph and Jörg Schreiner for excellent technical assistance. Data of the present study are part of the medical thesis of Thi Lan P. Tran. This work was supported by the European Commission integrated project (LSHM-CT-2004-005272/exgenesis) to B.V., by the German Research Foundation (DFG SCHU 1486/4-1 to E.S. and DFG WE4361/7-1 to P.W.) and by the Federal Ministry of Education and Research (BMBF 01EO1503).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

395_2019_717_MOESM1_ESM.docx (254 kb)
Supplementary material 1 (DOCX 253 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Swenja Kröller-Schön
    • 1
  • Thomas Jansen
    • 1
  • Thi Lan P. Tran
    • 1
  • Miroslawa Kvandová
    • 1
  • Sanela Kalinovic
    • 1
  • Matthias Oelze
    • 1
  • John F. KeaneyJr.
    • 6
  • Marc Foretz
    • 3
    • 4
    • 5
  • Benoit Viollet
    • 3
    • 4
    • 5
  • Andreas Daiber
    • 1
  • Sabine Kossmann
    • 2
  • Jeremy Lagrange
    • 2
  • Katie Frenis
    • 1
  • Philip Wenzel
    • 1
    • 2
  • Thomas Münzel
    • 1
  • Eberhard Schulz
    • 1
    Email author
  1. 1.Department of Cardiology 1, Center for CardiologyUniversitätsmedizin MainzMainzGermany
  2. 2.Center for Thrombosis and Hemostasis (CTH)Universitätsmedizin MainzMainzGermany
  3. 3.Inserm, U1016Institut CochinParisFrance
  4. 4.Cnrs, UMR8104ParisFrance
  5. 5.Univ Paris DescartesParisFrance
  6. 6.Division of Cardiovascular MedicineUMass Medical SchoolWorcesterUSA

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