Increased microvascular permeability in mice lacking Epac1 (Rapgef3)

R. K. Kopperud, C. Brekke Rygh, T. V. Karlsen, C. Krakstad, R. Kleppe, E. A. Hoivik, M. Bakke, O. Tenstad, F. Selheim, A. Lidén, L. Madsen, T. Pavlin, T. Taxt, K. Kristiansen, F. R E Curry, R. K. Reed, S. O. Døskeland

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Aim: Maintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signalling. This study probes the role of the cAMP mediators rap guanine nucleotide exchange factor 3 and 4 (Epac1 and Epac2) for in vivo control of microvascular macromolecule permeability under basal conditions. Methods: Epac1-/- and Epac2-/- C57BL/6J mice were produced and compared with wild-type mice for transvascular flux of radio-labelled albumin in skin, adipose tissue, intestine, heart and skeletal muscle. The transvascular leakage was also studied by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using the MRI contrast agent Gadomer-17 as probe. Results: Epac1-/- mice had constitutively increased transvascular macromolecule transport, indicating Epac1-dependent restriction of baseline permeability. In addition, Epac1-/- mice showed little or no enhancement of vascular permeability in response to atrial natriuretic peptide (ANP), whether probed with labelled albumin or Gadomer-17. Epac2-/- and wild-type mice had similar basal and ANP-stimulated clearances. Ultrastructure analysis revealed that Epac1-/- microvascular interendothelial junctions had constitutively less junctional complex. Conclusion: Epac1 exerts a tonic inhibition of in vivo basal microvascular permeability. The loss of this tonic action increases baseline permeability, presumably by reducing the interendothelial permeability resistance. Part of the action of ANP to increase permeability in wild-type microvessels may involve inhibition of the basal Epac1-dependent activity.

Original languageEnglish (US)
JournalActa Physiologica
DOIs
StateAccepted/In press - 2016

Fingerprint

Capillary Permeability
Permeability
Atrial Natriuretic Factor
Albumins
Guanine Nucleotide Exchange Factors
Microvessels
Blood Volume
Radio
Inbred C57BL Mouse
Contrast Media
Intestines
Adipose Tissue
Myocardium
Skeletal Muscle
Maintenance
Magnetic Resonance Imaging
Skin
gadomer 17

Keywords

  • Atrial natriuretic peptide
  • CAMP
  • Endothelial junction
  • Epac deletion (mouse)
  • Microvascular permeability (in vivo)
  • Rapgef

ASJC Scopus subject areas

  • Physiology

Cite this

Kopperud, R. K., Rygh, C. B., Karlsen, T. V., Krakstad, C., Kleppe, R., Hoivik, E. A., ... Døskeland, S. O. (Accepted/In press). Increased microvascular permeability in mice lacking Epac1 (Rapgef3). Acta Physiologica. https://doi.org/10.1111/apha.12697

Increased microvascular permeability in mice lacking Epac1 (Rapgef3). / Kopperud, R. K.; Rygh, C. Brekke; Karlsen, T. V.; Krakstad, C.; Kleppe, R.; Hoivik, E. A.; Bakke, M.; Tenstad, O.; Selheim, F.; Lidén, A.; Madsen, L.; Pavlin, T.; Taxt, T.; Kristiansen, K.; Curry, F. R E; Reed, R. K.; Døskeland, S. O.

In: Acta Physiologica, 2016.

Research output: Contribution to journalArticle

Kopperud, RK, Rygh, CB, Karlsen, TV, Krakstad, C, Kleppe, R, Hoivik, EA, Bakke, M, Tenstad, O, Selheim, F, Lidén, A, Madsen, L, Pavlin, T, Taxt, T, Kristiansen, K, Curry, FRE, Reed, RK & Døskeland, SO 2016, 'Increased microvascular permeability in mice lacking Epac1 (Rapgef3)', Acta Physiologica. https://doi.org/10.1111/apha.12697
Kopperud RK, Rygh CB, Karlsen TV, Krakstad C, Kleppe R, Hoivik EA et al. Increased microvascular permeability in mice lacking Epac1 (Rapgef3). Acta Physiologica. 2016. https://doi.org/10.1111/apha.12697
Kopperud, R. K. ; Rygh, C. Brekke ; Karlsen, T. V. ; Krakstad, C. ; Kleppe, R. ; Hoivik, E. A. ; Bakke, M. ; Tenstad, O. ; Selheim, F. ; Lidén, A. ; Madsen, L. ; Pavlin, T. ; Taxt, T. ; Kristiansen, K. ; Curry, F. R E ; Reed, R. K. ; Døskeland, S. O. / Increased microvascular permeability in mice lacking Epac1 (Rapgef3). In: Acta Physiologica. 2016.
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abstract = "Aim: Maintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signalling. This study probes the role of the cAMP mediators rap guanine nucleotide exchange factor 3 and 4 (Epac1 and Epac2) for in vivo control of microvascular macromolecule permeability under basal conditions. Methods: Epac1-/- and Epac2-/- C57BL/6J mice were produced and compared with wild-type mice for transvascular flux of radio-labelled albumin in skin, adipose tissue, intestine, heart and skeletal muscle. The transvascular leakage was also studied by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using the MRI contrast agent Gadomer-17 as probe. Results: Epac1-/- mice had constitutively increased transvascular macromolecule transport, indicating Epac1-dependent restriction of baseline permeability. In addition, Epac1-/- mice showed little or no enhancement of vascular permeability in response to atrial natriuretic peptide (ANP), whether probed with labelled albumin or Gadomer-17. Epac2-/- and wild-type mice had similar basal and ANP-stimulated clearances. Ultrastructure analysis revealed that Epac1-/- microvascular interendothelial junctions had constitutively less junctional complex. Conclusion: Epac1 exerts a tonic inhibition of in vivo basal microvascular permeability. The loss of this tonic action increases baseline permeability, presumably by reducing the interendothelial permeability resistance. Part of the action of ANP to increase permeability in wild-type microvessels may involve inhibition of the basal Epac1-dependent activity.",
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T1 - Increased microvascular permeability in mice lacking Epac1 (Rapgef3)

AU - Kopperud, R. K.

AU - Rygh, C. Brekke

AU - Karlsen, T. V.

AU - Krakstad, C.

AU - Kleppe, R.

AU - Hoivik, E. A.

AU - Bakke, M.

AU - Tenstad, O.

AU - Selheim, F.

AU - Lidén, A.

AU - Madsen, L.

AU - Pavlin, T.

AU - Taxt, T.

AU - Kristiansen, K.

AU - Curry, F. R E

AU - Reed, R. K.

AU - Døskeland, S. O.

PY - 2016

Y1 - 2016

N2 - Aim: Maintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signalling. This study probes the role of the cAMP mediators rap guanine nucleotide exchange factor 3 and 4 (Epac1 and Epac2) for in vivo control of microvascular macromolecule permeability under basal conditions. Methods: Epac1-/- and Epac2-/- C57BL/6J mice were produced and compared with wild-type mice for transvascular flux of radio-labelled albumin in skin, adipose tissue, intestine, heart and skeletal muscle. The transvascular leakage was also studied by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using the MRI contrast agent Gadomer-17 as probe. Results: Epac1-/- mice had constitutively increased transvascular macromolecule transport, indicating Epac1-dependent restriction of baseline permeability. In addition, Epac1-/- mice showed little or no enhancement of vascular permeability in response to atrial natriuretic peptide (ANP), whether probed with labelled albumin or Gadomer-17. Epac2-/- and wild-type mice had similar basal and ANP-stimulated clearances. Ultrastructure analysis revealed that Epac1-/- microvascular interendothelial junctions had constitutively less junctional complex. Conclusion: Epac1 exerts a tonic inhibition of in vivo basal microvascular permeability. The loss of this tonic action increases baseline permeability, presumably by reducing the interendothelial permeability resistance. Part of the action of ANP to increase permeability in wild-type microvessels may involve inhibition of the basal Epac1-dependent activity.

AB - Aim: Maintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signalling. This study probes the role of the cAMP mediators rap guanine nucleotide exchange factor 3 and 4 (Epac1 and Epac2) for in vivo control of microvascular macromolecule permeability under basal conditions. Methods: Epac1-/- and Epac2-/- C57BL/6J mice were produced and compared with wild-type mice for transvascular flux of radio-labelled albumin in skin, adipose tissue, intestine, heart and skeletal muscle. The transvascular leakage was also studied by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using the MRI contrast agent Gadomer-17 as probe. Results: Epac1-/- mice had constitutively increased transvascular macromolecule transport, indicating Epac1-dependent restriction of baseline permeability. In addition, Epac1-/- mice showed little or no enhancement of vascular permeability in response to atrial natriuretic peptide (ANP), whether probed with labelled albumin or Gadomer-17. Epac2-/- and wild-type mice had similar basal and ANP-stimulated clearances. Ultrastructure analysis revealed that Epac1-/- microvascular interendothelial junctions had constitutively less junctional complex. Conclusion: Epac1 exerts a tonic inhibition of in vivo basal microvascular permeability. The loss of this tonic action increases baseline permeability, presumably by reducing the interendothelial permeability resistance. Part of the action of ANP to increase permeability in wild-type microvessels may involve inhibition of the basal Epac1-dependent activity.

KW - Atrial natriuretic peptide

KW - CAMP

KW - Endothelial junction

KW - Epac deletion (mouse)

KW - Microvascular permeability (in vivo)

KW - Rapgef

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