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A critical role for Lyn kinase in strengthening endothelial integrity and barrier function.
- Source :
-
Blood [Blood] 2013 Dec 12; Vol. 122 (25), pp. 4140-9. Date of Electronic Publication: 2013 Oct 09. - Publication Year :
- 2013
-
Abstract
- The Src family kinases (SFKs) c-Src and Yes mediate vascular leakage in response to various stimuli including lipopolysaccharide (LPS) and vascular endothelial growth factor (VEGF). Here, we define an opposing function of another SFK, Lyn, which in contrast to other SFKs, strengthens endothelial junctions and thereby restrains the increase in vascular permeability. Mice lacking Lyn displayed increased mortality in LPS-induced endotoxemia and increased vascular permeability in response to LPS or VEGF challenge compared with wild-type littermates. Lyn knockout mice repopulated with wild-type bone marrow-derived cells have higher vascular permeability than wild-type mice, suggesting a role of endothelial Lyn in the maintenance of the vascular barrier. Small interfering RNA-mediated down-regulation of Lyn disrupted endothelial barrier integrity, whereas expression of a constitutively active mutant of Lyn enhanced the barrier. However, down-regulation of Lyn did not affect LPS-induced endothelial permeability. We demonstrate that Lyn association with focal adhesion kinase (FAK) and phosphorylation of FAK at tyrosine residues 576/577 and 925 were required for Lyn-dependent stabilization of endothelial adherens junctions. Thus, in contrast to c-Src and Yes, which increase vascular permeability in response to stimuli, Lyn stabilizes endothelial junctions through phosphorylation of FAK. Therefore, therapeutics activating Lyn kinase may strengthen the endothelial barrier junction and hence have anti-inflammatory potential.
- Subjects :
- Adherens Junctions genetics
Animals
Capillary Permeability drug effects
Down-Regulation drug effects
Down-Regulation genetics
Endothelial Cells cytology
Endothelium, Vascular cytology
Focal Adhesion Kinase 1 genetics
Focal Adhesion Kinase 1 metabolism
Human Umbilical Vein Endothelial Cells
Humans
Lipopolysaccharides pharmacology
Mice
Mice, Knockout
Phosphorylation drug effects
Phosphorylation genetics
src-Family Kinases genetics
Adherens Junctions enzymology
Capillary Permeability physiology
Endothelial Cells enzymology
Endothelium, Vascular enzymology
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 122
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 24108461
- Full Text :
- https://doi.org/10.1182/blood-2013-03-491423