Revealing roles of angiopoietin-4 in eye fluid homeostasis and angiopoietin-2443 in cancer in mice

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Leena Palotie Auditorium (101A), Main building of the medical campus, Aapistie 5A

Topic of the dissertation

Revealing roles of angiopoietin-4 in eye fluid homeostasis and angiopoietin-2443 in cancer in mice

Doctoral candidate

Master of Science Emmi Kapiainen

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM and Hypoxia Research Unit

Subject of study

Biochemistry and Molecular Medicine

Opponent

Adjunct Professor Yvonne Reiss, Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt am Main, Germany

Custos

Professor Lauri Eklund, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu

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Mouse model studies reveal novel functions of angiopoietin-2443 and angiopoietin-4 in tissues

Functioning blood circulation and fluid drainage mechanisms are essential systems in all organs. The endothelial Tie2 tyrosine kinase receptor and its angiopoietin (Angpt) ligands regulate both developmental angiogenesis and vascular remodeling. While Angpt1 and Angpt2 have been in the center of previous research, this thesis focused on determining the importance of two less characterized Angpt ligands, Angpt4 and an alternatively spliced variant of Angpt2, Angpt2443, by using various genetically modified mouse models.

In the anterior eye, a specialized vessel called the Schlemm’s canal (SC) Tie2-dependently transports aqueous humor from the anterior chamber to the blood circulation, maintaining optimal intraocular pressure. While Angpt4 deletion alone was dispensable for SC maintenance and Angpt4 deletion did not aggravate the effects of Angpt1 deletion, deletion of both Angpt2 and Angpt4 caused severe SC defects, which led to glaucoma-like changes in the eye. Angpt2 deletion caused more subtle effects on SC function, yet Angpt2 was required for both normal SC and corneolimbal vasculature morphology. In the posterior eye, Angpt4 was discovered to regulate vein remodeling in the retina, and Angpt4 deletion caused pathological intraretinal fluid accumulation. Similar retinal venous abnormalities were also found in knock-in mice expressing Angpt2443, indicating increased Tie2 antagonism by Angpt2443. The in vivo importance of Angpt2443 was also investigated using three mouse cancer models. Angpt2443 was found to have differential effects on mammary gland tumors and lung metastases depending on the tumor microenvironment and availability of metastatic cells. In Tie2-expressing primary tumors, Angpt2443 reduced tumor vasculature, primary tumor growth, and subsequent metastasis, but when the circulating metastatic cell load was more equal, Angpt2443 expression had a destabilizing effect on lung endothelium integrity that associated with increased metastases.

The results of this thesis establish novel roles for Angpt4 in eye fluid homeostasis, give new insights on the function of Angpt2443, and advance our understanding of the relatively complex Angpt/Tie2 signaling pathway. Novel medicines targeting the Angpt/Tie pathway with indications in ophthalmological diseases and cancer are currently intensely investigated, and better understanding of the roles of Angpt4 and Angpt2443 in tissues can facilitate the development of new treatments in the future.
Last updated: 7.11.2022