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VASCULAR BIOLOGY

The role of VASP in regulation of cAMP- and Rac 1-mediated endothelial barrier stabilization

¹Institute of Anatomy and Cell Biology and ²Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany

Submitted 27 June 2007 ; accepted in final form 2 November 2007

Regulation of actin dynamics is critical for endothelial barrier functions. We provide evidence that the actin-binding protein vasodilator-stimulated phosphoprotein (VASP) is required for endothelial barrier maintenance. Baseline permeability was significantly increased in VASP-deficient (VASP^–/–) microvascular myocardial endothelial cells (MyEnd) in the absence of discernible alterations of immunostaining for adherens and tight junctions. We tested whether VASP is involved in the endothelium-stabilizing effects of cAMP or Rac 1. Forskolin and rolipram (F/R) to increase cAMP and cytotoxic necrotizing factor 1 (CNF-1) to activate Rac 1 were equally efficient to stabilize barrier functions in VASP^–/– and wild-type (wt) cells. In wt cells, VASP was phosphorylated in response to F/R but did not localize to intercellular junctions. In contrast, CNF-1 and expression of constitutively active Rac 1 induced translocation of VASP to cell borders in wt cells, where it colocalized with active Rac 1. In VASP^–/– cells, Rac 1 activity was reduced to 0.4 of wt levels in controls and increased 20-fold in response to CNF-1 compared with 7-fold activation in wt cells. Moreover, inactivation of Rac 1 by lethal toxin led to a greater increase of permeability compared with wt cells. All these data suggest that VASP is involved in the regulation of Rac 1 activity. Taking these findings together, our study indicates that VASP at least in part stabilizes endothelial barrier functions by control of Rho-family GTPases.

endothelial barrier functions; vasodilator-stimulated phosphoprotein; Rho guanosine 5'-triphosphatase; adenosine 3',5'-cyclic monophosphate

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