Vasodilator-stimulated phosphoprotein deficiency potentiates PAR-1-induced increase in endothelial permeability in mouse lungs

Jasmina Profirovic, Jingyan Han, Alexandra V. Andreeva, Radu F. Neamu, Sasha Pavlovic, Stephen M. Vogel, Ulrich Walter, Tatyana A. Voyno-Yasenetskaya

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5 Scopus citations

Abstract

Vasodilator-stimulated phosphoprotein (VASP) is implicated in the protection of the endothelial barrier in vitro and in vivo. The function of VASP in thrombin signaling in the endothelial cells (ECs) is not known. For the first time we studied the effects of VASP deficiency on EC permeability and pulmonary vascular permeability in response to thrombin receptor stimulation. We provided the evidence that VASP deficiency potentiates the increase in endothelial permeability induced by activation of thrombin receptor in cultured human umbilical vein endothelial cells (HUVECs) and isolated mouse lungs. Using transendothelial resistance measurement, we showed that siRNA-mediated VASP downregulation in HUVECs leads to a potentiation of thrombin- and protease-activated receptor 1 (PAR-1) agonist-induced increase in endothelial permeability. Compared to control cells, VASP-deficient HUVECs had delayed endothelial junctional reassembly and abrogated VE-cadherin cytoskeletal anchoring in the recovery phase after thrombin stimulation, as demonstrated by immunofluorescence studies and cell fractionation analysis, respectively. Measurement of the capillary filtration coefficient in isolated mouse lungs demonstrated that VASP-/- mice have increased microvascular permeability in response to infusion with PAR-1 agonist compared to wild type mice. Lack of VASP led to decreased Rac1 activation both in VASP-deficient HUVECs after thrombin stimulation and VASP-/- mouse lungs after PAR-1 agonist infusion, indicating that VASP effects on thrombin signaling may be correlated with changes in Rac1 activity. This study demonstrates that VASP may play critical and complex role in the regulation of thrombin-dependent disruption of the endothelial barrier function.

Original languageEnglish
Pages (from-to)1255-1264
Number of pages10
JournalJournal of Cellular Physiology
Volume226
Issue number5
DOIs
StatePublished - May 1 2011

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    Profirovic, J., Han, J., Andreeva, A. V., Neamu, R. F., Pavlovic, S., Vogel, S. M., Walter, U., & Voyno-Yasenetskaya, T. A. (2011). Vasodilator-stimulated phosphoprotein deficiency potentiates PAR-1-induced increase in endothelial permeability in mouse lungs. Journal of Cellular Physiology, 226(5), 1255-1264. https://doi.org/10.1002/jcp.22453