Increased microvascular permeability in mice lacking Epac1 (Rapgef3).
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.



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.



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.



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.
Department of Biomedicine, University of Bergen, Bergen, Norway.|Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.
R K
RK
Kopperud
Department of Biomedicine, University of Bergen, Bergen, Norway.
C Brekke
CB
Rygh
Department of Biomedicine, University of Bergen, Bergen, Norway.
T V
TV
Karlsen
Department of Biomedicine, University of Bergen, Bergen, Norway.
C
C
Krakstad
Department of Biomedicine, University of Bergen, Bergen, Norway.
R
R
Kleppe
Department of Biomedicine, University of Bergen, Bergen, Norway.
E A
EA
Hoivik
Department of Biomedicine, University of Bergen, Bergen, Norway.
M
M
Bakke
Department of Biomedicine, University of Bergen, Bergen, Norway.
O
O
Tenstad
Department of Biomedicine, University of Bergen, Bergen, Norway.
F
F
Selheim
Department of Biomedicine, University of Bergen, Bergen, Norway.
Å
Å
Lidén
Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Biology, University of Copenhagen, Copenhagen, Denmark.
L
L
Madsen
Department of Biomedicine, University of Bergen, Bergen, Norway.
T
T
Pavlin
Department of Biomedicine, University of Bergen, Bergen, Norway.
T
T
Taxt
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
K
K
Kristiansen
Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA, USA.
F-R E
FE
Curry
Department of Biomedicine, University of Bergen, Bergen, Norway.|Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.
R K
RK
Reed
Department of Biomedicine, University of Bergen, Bergen, Norway.
S O
SO
Døskeland
D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse
Epac deletion (mouse); Rapgef; atrial natriuretic peptide; cAMP; endothelial junction; microvascular permeability (in vivo)