Controlling angiogenesis : Functional studies of angiomotin
Year: 2007
Type: dissertation
Abstract: The expansion of a blood circulatory network by the process of \nangiogenesis is essential for embryonic as well as postnatal growth. \nDeregulated blood vessel formation may also negatively contribute to the \npathogenesis of diseases, e.g. cancer and diabetic retinopathy. \nFurthermore, compounds that interfere with angiogenesis signalling \npathways have shown great promise when used in clinical trials for \npatients suffering from cancer or macular degeneration. \n \n \n \nThe formation of a functional blood vessel involves several distinct \nsteps. Cells of the vessel wall, i.e. endothelial cells, extend filopodia \nthat sense pro-angiogenic signals and direct migration and the formation \nof the vessel network. Circulation is established when two endothelial \nsprouts fuse and form a continuous lumen. Angiomotin has previously been \nimplicated to play a role in endothelial migration and to be a possible \ntarget for anti-angiogenic therapy. The aim of this thesis was to \ninvestigate the biological role of angiomotin during vascular development \nand to elucidate the signalling pathways involved. \n \n \n \nIn this thesis it is demonstrated that the angiomotin gene is expressed \nas two isoforms with distinct functions. The shorter isoform, \np80-angiomotin, is expressed during the migratory phase of retinal \nangiogenesis, whereas the other isoform, p130-angiomotin, is expressed \nduring and after vessel maturation. In vitro, these isoforms exhibit \nopposite functions. For instance, p80-angiomotin promotes cell migration \nwhereas p130-angiomotin promotes actin fibre formation and cell contacts. \nIt is further shown that p80-angiomotin expression removes \np130-angiomotin from cell junctions resulting in a migratory switch. \n \n \n \nThe angiomotin signalling pathway was analysed by identifying binding \nproteins by two different approaches, peptide pull down and yeast \ntwo-hybrid screening. Data are presented demonstrating that the \nPDZ-binding domain of angiomotin binds to a polarity protein complex as \nwell as to a Rho-GEF, which has previously been shown to mediate \nendothelial cell migration. These findings argue that angiomotin acts as \na scaffold for proteins regulating cell polarity and GTPase activity. \n \n \n \nThe biological role of angiomotin during mouse and zebrafish \nembryogenesis was also studied. Genetic ablation of angiomotin in the \nmouse results in vascular defects in the intersomitic region as well as \ndilated vessels in the brain and embryonic lethality after E11. \nFurthermore, knockdown of angiomotin in zebrafish impaired the migration \nof intersegmental vessels and caused dilation of vessels in the brain, \nconfirming the phenotype found in the mouse. It is further shown that \nangiomotin deficient endothelial cells have an intact proliferative \nresponse to VEGF but exhibit defects in migration. \n \n \n \nTaken together, these data indicate that angiomotin is essential for \nnormal embryonic vessel formation and that it may affect directional cell \nmigration by controlling cell polarity and GTPase activity.
Source: Figshare
Author: Mira Ernkvist
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1551157694