title: Lack of netrin-4 modulates pathologic neovascularization in the eye.
abstract: Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4(-/-) mice with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), mimicking hypoxia-mediated neovascularization and inflammatory mediated angiogenesis. The basement membrane protein netrin-4 was found to be localised to mature retinal blood vessels. Netrin-4, but not netrin-1 mRNA expression, increased in response to relative hypoxia and recovered to normal levels at the end of blood vessel formation. No changes in the retina were found in normoxic Ntn-4(-/-) mice. In OIR, Ntn-4(-/-) mice initially displayed larger avascular areas which recovered faster to revascularization. Ganzfeld electroretinography showed faster recovery of retinal function in Ntn-4(-/-) mice. Expression of netrin receptors, Unc5H2 (Unc-5 homolog B, C. elegans) and DCC (deleted in colorectal carcinoma), was found in Müller cells and astrocytes. Laser-induced neovascularization in Nnt-4(-/-) mice did not differ to that in the controls. Our results indicate a role for netrin-4 as an angiogenesis modulating factor in O2-dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization.
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Kociok
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Sergio
authors.initials: S
authors.lastname: Crespo-Garcia
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.|Department of Ophthalmology, Peking University, People's Hospital, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Sabrina V
authors.initials: SV
authors.lastname: Klein
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Nürnberg
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Reichhart
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Sergej
authors.initials: S
authors.lastname: Skosyrski
authors.affiliation: Institute for Dental Research and Oral Musculoskeletal Biology and Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Moritz
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Anna-Karina
authors.initials: AK
authors.lastname: Maier
authors.affiliation: Department of Ophthalmology, Upstate Medical University, Syracuse, New York, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brunken
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Strauß
authors.affiliation: Institute for Dental Research and Oral Musculoskeletal Biology and Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Koch
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Joussen
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005128:Eye Diseases / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology*; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000075386:Netrin Receptors; D000075385:Netrins; D009457:Neuroglia / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000175:diagnosis / Q000209:etiology / Q000473:pathology; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075385:Netrins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; C416214:Ntn4 protein, mouse; C000617307:Unc5b protein, mouse