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|Title: ||ARHGAP18: A regulator of sprouting angiogenesis and junctional integrity|
|Authors: ||Chang, Garry Hoi-Kai|
|Issue Date: ||30-Jun-2015|
|Publisher: ||University of Sydney|
Sydney Medical School
|Abstract: ||The formation of the vascular network requires a tightly controlled regulation of proangiogenic and stabilising signals, including VEGF and the endothelial junctions respectively. Perturbation of this balance can result in dysregulated blood vessel morphogenesis and drive pathologies, including cancer. The Rho GTPases are major signaling regulators of the cytoskeleton and control functions such as cell migration and adhesion.
We have identified that ARHGAP18 controls RhoC activity and functions as an endogenous negative regulator of angiogenesis by limiting pro-angiogeneic signaling and promoting vascular stability. Loss of ARHGAP18 promotes EC hypersprouting during zebrafish and murine retinal vessel development and enhances tumour vascularization and growth. Endogenous ARHGAP18 acts specifically via RhoC and relocalizes to the angiogenic and destabilized EC junctions in a ROCK dependent manner, where it is important in reaffirming stable EC junctions and suppressing tip cell behavior, at least partially through regulation of tip cell genes, Dll4, Flk-1 and Flt-4. The molecular mechanism governing the activation and translocation of ARHGAP18 to the cell periphery is at its infancy but phosphorylation and association with cortactin are involved.
Aberrant Ras signaling is associated with cancer and vascular pathologies, such as angiosarcomas. Chronic HRas activation induces a transformed-like phenotype, with fibroblastic cell phenotype, increased cell migration and sprouting, dysregulated endothelial junctions and a partial alteration of endothelial-to-mesenchymal markers. This is associated with but not dependent on downregulation of ARHGAP18 expression. These findings highlight ARHGAP18 as a specific RhoGAP to fine-tune vascular morphogenesis, acting as a negative regulator to limit tip cell formation and promote junctional integrity to stabilize the angiogenic architecture.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (Open Access)|
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|CHANG Garry Hoi-kai - Final Thesis.pdf||Thesis||47.93 MB||Adobe PDF|
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