Increased microvascular permeability in mice lacking Epac1 (Rapgef3).
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.
['Kopperud|R K|RK|', 'Rygh|C Brekke|CB|', 'Karlsen|T V|TV|', 'Krakstad|C|C|', 'Kleppe|R|R|', 'Hoivik|E A|EA|', 'Bakke|M|M|', 'Tenstad|O|O|', 'Selheim|F|F|', 'Lidén|Å|Å|', 'Madsen|L|L|', 'Pavlin|T|T|', 'Taxt|T|T|', 'Kristiansen|K|K|', 'Curry|F-R E|FE|', 'Reed|R K|RK|', 'Døskeland|S O|SO|']
D000818:Animals D015153:Blotting, Western D002199:Capillary Permeability D004195:Disease Models, Animal D005260:Female D020662:Guanine Nucleotide Exchange Factors D007150:Immunohistochemistry D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D046529:Microscopy, Electron, Transmission
cAMP atrial natriuretic peptide Epac deletion (mouse) Rapgef endothelial junction microvascular permeability (in vivo)