Laurent Loufrani*, Charles R White*, Guang-Liang Jiang, Hazel Y. Stevens, and John A. Frangos.
Shear-Induced dissociation of Gaq-PECAM-1 Complexes Localized to the Endothelial Cell-Cell Junction.
In Submission to PMSAs the inner lining of the vessel wall, vascular endothelial cells are poised to act as a signal transduction interface for hemodynamic forces. The molecular mechanisms of the primary force sensing elements of the cell, and cascade of events that are involved in the mechanochemical signal pathway remain unclear. The activation of membrane bound G protein Gaq, has been recognized as a mediator of flow-induced endothelial response. Platelet endothelial cell adhesion molecule-1 (PECAM-1) has also been shown to rapidly respond to shear stress. This is the first study to demonstrate the co-localization of membrane associated Gaq to the cell-cell junction in a complex with PECAM-1. In primary human umbilical vein endothelial cells, temporal gradients in shear stress lead to a rapid disassociation and re-association of the Gaq-PECAM-1 complex within 15 sec (0.65 ± 0.059 ratio Gaq/PECAM-1 versus Sham control), whereas transitioning fluid flow devoid of temporal gradients does not disrupt the complex (1.04 ± 0.08 ratio Gq/PECAM-1 versus Sham control). Inhibition of protein kinases and tyrosine kinases completely eliminated impulse flow induced Gaq-PECAM-1 disassociation and PECAM-1 phosphorylation. Taken to together, this data may represent a missing link between the primary force sensing elements of the cell, and the down stream mechanochemical transduction pathway.
* Drs White and Loufrani are joint primary authors of this work.