title: A lymphatic defect causes ocular hypertension and glaucoma in mice.
abstract: Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Increased intraocular pressure (IOP) due to impaired aqueous humor drainage is a major risk factor for the development of glaucoma. Here, we demonstrated that genetic disruption of the angiopoietin/TIE2 (ANGPT/TIE2) signaling pathway results in high IOP, buphthalmos, and classic features of glaucoma, including retinal ganglion degeneration and vision loss. Eyes from mice with induced deletion of Angpt1 and Angpt2 (A1A2Flox(WB) mice) lacked drainage pathways in the corneal limbus, including Schlemm's canal and lymphatic capillaries, which share expression of the PROX1, VEGFR3, and FOXC family of transcription factors. VEGFR3 and FOXCs have been linked to lymphatic disorders in patients, and FOXC1 has been linked to glaucoma. In contrast to blood endothelium, in which ANGPT2 is an antagonist of ANGPT1, we have shown that both ligands cooperate to regulate TIE2 in the lymphatic network of the eye. While A1A2Flox(WB) mice developed high IOP and glaucoma, expression of ANGPT1 or ANGPT2 alone was sufficient for ocular drainage. Furthermore, we demonstrated that loss of FOXC2 from lymphatics results in TIE2 downregulation, suggesting a mechanism for ocular defects in patients with FOXC mutations. These data reveal a pathogenetic and molecular basis for glaucoma and demonstrate the importance of angiopoietin ligand cooperation in the lymphatic endothelium.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Thomson
authors.forename: Stefan
authors.initials: S
authors.lastname: Heinen
authors.forename: Marie
authors.initials: M
authors.lastname: Jeansson
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Anees
authors.initials: A
authors.lastname: Fatima
authors.forename: Hoon-Ki
authors.initials: HK
authors.lastname: Sung
authors.forename: Tuncer
authors.initials: T
authors.lastname: Onay
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: Ann
authors.initials: A
authors.lastname: Flenniken
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Gale
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
authors.forename: Amani
authors.initials: A
authors.lastname: Fawzi
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liu
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics*; D042702:Angiopoietin-2 / Q000235:genetics; D000818:Animals; D001082:Aqueous Humor; D002469:Cell Separation; D004195:Disease Models, Animal; D015536:Down-Regulation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005901:Glaucoma / Q000473:pathology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007429:Intraocular Pressure; D008024:Ligands; D008208:Lymphatic System / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009798:Ocular Hypertension / Q000473:pathology*; D042787:Receptor, TIE-2 / Q000235:genetics*; D014129:Trabecular Meshwork / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D018398:Homeodomain Proteins; D008024:Ligands; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3