%0 Generic
%A Korhonen, Hanna
%D 2008
%F heidok:8963
%K NO , G-Proteinendothelium , mouse , anaphylaxis , NO , G-protein
%R 10.11588/heidok.00008963
%T Analysis of Gq/G11 and G12/G13 mediated signalling in the endothelial functions
%U https://archiv.ub.uni-heidelberg.de/volltextserver/8963/
%X In this study, I analyzed the role of GPCR signalling pathways mediated by Gq/G11 and G12/G13 in the functions of the adult endothelium. To achieve endothelium specific deletion of G-alpha-q/11 and G-alpha-12/13, I crossed an inducible Tie2-Cre mouse line with mice carrying floxed alleles of the genes encoding G-alpha-q (Gnaq) and G-alpha-13 (Gna13) in G-alpha-11- or G-alpha-12-deficient backgrounds, respectively. After induction of Cre with tamoxifen, I observed endothelium specific recombination in various organs, excluding brain vessels and aorta. I confirmed the loss of G-alpha-q/11 and G-alpha-12/13 in pulmonary endothelial cells isolated from the respective mouse lines and was able to show that the phosphorylation of MLC in primary pulmonary endothelial cells depended on G-alpha-q/11, while G-alpha-12/13 pathway was less important. When stimulated with histamine or PAF, endothelial NO production was blocked in the absence of G-alpha-q/11. In vivo the lack of G-alpha-q/11 in endothelial cells led to reduced vascular permeability, which was consistent with in vitro MLC phosphorylation results. G-alpha-q/11 was necessary for normal hypotensive response to histamine stimulation, and for PAF-induced shock. Sensitized endothelial cell specific G-alpha-q/11 KO mice were resistant to development of anaphylactic shock when challenged with allergen. In addition, endothelial G-alpha-q/11 KO mice showed reduced leukocyte rolling in trauma induced acute inflammation. In conclusion, I was able to show that endothelial G-alpha-q/11 is a regulator of endothelial cell contraction and endothelial barrier function in response to various inflammatory mediators, and that it is critically involved in systemic anaphylactic reactions. These data suggest that Gq/G11-mediated signalling pathway in endothelial cells is a promising target to prevent or to treat anaphylactic shock.