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G. Gnanaguru, G. A. Pinzón-Duarte, G. Bachay, W. J. Brunken; Laminins Are Key Regulators of Retinal Angiogenesis and Vascular Integrity. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2928.
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© ARVO (1962-2015); The Authors (2016-present)
Laminins are the key organizing molecules of BMs including the ILM and vascular BM. We analyzed the role of laminin β2 and γ3 in angiogenesis and vascular integrity.
Expression of laminin β2 and γ3 was studied from P0 to P16 using standard techniques. The distribution of vascular components was studied in wild type and mutant retinas. Astrocytes and microglia distributions were determined with cell specific markers and correlated with angiogenesis. We used immunohistochemistry to assay blood vessel integrity and aquaporin-4 distribution. Organotypic cultures of WT and mutant retinas were used to study astrocyte migration.
Laminin β2 chain is expressed over the ILM from P0 through adult and ubiquitously in vascular BM. In contrast, laminin γ3 has more limited expression in the ILM and is confined to microvessels and veins. BM formation and subsequently astrocyte distribution and angiogenesis are disrupted in the β2 null and β2γ3 compound null animal. To further understand the molecular mechanisms of astrocyte migration, organotypic cultures of both WT and mutant retina were studied. Astrocytes are regularly distributed over the WT retinal surface, with the exceptions of regions where the ILM was surgically disrupted; no astrocytes were found overlaying these regions. Suggesting that the ILM is an important haptotactic surface for astrocyte migration. The observation that, astrocyte migration is disoriented in laminin mutants supports this hypothesis. During normal development, hyaloid vessels regress and microglia mediate their phagocytosis. In the β2 null and β2γ3 null retinas, hyaloid vessels persist and few active microglia are associated with the hyaloid vessels. However, microglia are associated with the ONL and OPL in the mutant consistent with increased neurodegeneration. Blood vessel integrity, measured by serum leakage, is also disrupted as is aquaporin channel distribution.
These data demonstrate that laminin β2 and γ3 plays a critical role in ILM formation, angiogenesis and vessel integrity. They also suggest that laminin and laminin receptors may be used to regulate neovascular events in the retina.
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