Critical role of Cdc42 in mediating endothelial barrier protection in vivo
Φόρτωση...
Ημερομηνία
Συγγραφείς
Ramchandran, R.
Mehta, D.
Vogel, S. M.
Mirza, M. K.
Kouklis, P.
Malik, A. B.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Am J Physiol Lung Cell Mol Physiol
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
Activation of the Rho GTPase Cdc42 has been shown in endothelial cell monolayers to prevent disassembly of interendothelial junctions and the increase in endothelial permeability. Here, we addressed the in vivo role of Cdc42 activity in mediating endothelial barrier protection in lungs by generating mice expressing the dominant active mutant V12Cdc42 protein in vascular endothelial cells targeted via the VE-cadherin promoter. These mice developed normally and exhibited constitutively active GTP-bound Cdc42. The increase in lung vascular permeability and gain in tissue water content in response to intraperitoneal lipopolysaccharide challenge (7 mg/kg) were markedly attenuated in the transgenic mice. To address the basis of the protective effect, we observed that expression of V12Cdc42 mutant in endothelial monolayers reduced the decrease in transendothelial electrical resistance, a measure of opening of interendothelial junctions, thus indicating that Cdc42 activity preserved junctional integrity. RhoA activity in V12Cdc42-expressing endothelial monolayers was reduced compared with untransfected cells, suggesting that activated Cdc42 functions by counteracting the canonical RhoA-mediated mechanism of endothelial hyperpermeability. Therefore, Cdc42 activity of microvessel endothelial cells is a critical determinant of junctional barrier restrictiveness and may represent a means of therapeutically modulating increased lung vascular permeability and edema formation.
Περιγραφή
Λέξεις-κλειδιά
Animals, Antigens, CD/genetics, Blood-Air Barrier/*metabolism/pathology, Cadherins/genetics, Capillary Permeability/drug effects/genetics, Electric Impedance, Endothelial Cells/*metabolism/pathology, Genes, Dominant/genetics, Intercellular Junctions/genetics/*metabolism/pathology, Lipopolysaccharides/toxicity, Mice, Mice, Transgenic, *Mutation, Missense, Promoter Regions, Genetic/genetics, Pulmonary Edema/chemically induced/genetics/*metabolism/pathology, cdc42 GTP-Binding Protein/genetics/*metabolism, rho GTP-Binding Proteins/genetics/metabolism
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/18515405
http://ajplung.physiology.org/content/295/2/L363.full.pdf
http://ajplung.physiology.org/content/295/2/L363.full.pdf
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής