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The role of endothelial PI3 kinase activity and IQGAP1 in regulation of lymphocyte diapedesis Open Access


Other title
Endothelial cells
PI3 kinase
Lymphocyte transendothelial migration
Type of item
Degree grantor
University of Alberta
Author or creator
Nakhaei-Nejad, Maryam
Supervisor and department
Murray, Allan G (Medicine)
Examining committee member and department
Touret, Nicolas (Biochemistry)
Jahroudi, Nadia (Medicine)
Tibbles, Lee Anne (Physiology and Pharmacology)
Vliagoftis, Harissios (Medicine)
Department of Medicine

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Leukocyte extravasation is a fundamental process of the inflammatory responses. The mechanisms that control remodelling of endothelial (EC) shape and adhesive contacts during leukocyte transendothelial migration (TEM) are not completely understood. We studied the role of EC phosphatidylinositol 3-kinase (PI3K) activity in lymphocyte TEM under shear stress conditions. Inhibition of EC PI3K activity by its pan inhibitors decreased lymphocyte diapedesis in a step after VE-cadherin opening. The importance of PI3K catalytic isoforms (p110α, p110β, p110δ and p110γ) were studied in TEM. Treatment of EC with isoform inhibitors of p110β, p110δ and p110γ did not affect lymphocyte TEM. Inhibition of p110α activity or expression reduced lymphocyte diapedesis. PI3K activity was measured in EC exposed to shear stress alone or shear stress on cells where ICAM-1 or VCAM-1 were cross-linked. The most significant effect was seen in cells cross-linked with ICAM-1 and exposed to shear stress. This suggests that cooperation of shear-induced mechanotransduction and ICAM-1 during leukocyte interaction with EC facilitates leukocyte diapedesis by inducing PI3K. We hypothesized that Rho GTP proteins downstream of PI3K activity are involved in leukocyte TEM. We studied the role of IQGAP1, a Rac1/Cdc42 effector, during lymphocyte TEM. EC IQGAP1 knockdown decreases both microtubule (MT) tethered to the adherens junction (AJ) and lymphocyte TEM. Similarly, loss of AJ-associated MT induced by brief nocodazole (ND) treatment decreases lymphocyte TEM. Neither intervention affected leukocyte migration to the interendothelial junctions. These data indicate that IQGAP1 contributes to MT stability at endothelial junctions and is involved in the junction remodelling required for efficient lymphocyte diapedesis. We studied a candidate Rho guanine nucleotide exchange factor named FGD5 upstream of IQGAP1. Inhibition of FGD5 expression resulted in more sensitivity to apoptotic stimuli and a higher rate of apoptosis in resting conditions. Thus, we could not study the importance of FGD5 in lymphocyte TEM. Further characterization of FGD5 knockdown cells showed that they do not respond to VEGF signalling. These results suggest that FGD5 might play an important role in growth factor–mediated EC survival.
License granted by Maryam Nakhaei-Nejad ( on 2011-08-25T22:41:21Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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