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
