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W. J. Brunken, Y. Li, G. Gnanaguru, G. Pinzón-Duarte; Retinal Vasculature Develops Abnormally in Laminin Null Mice: A Novel ROP Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):519.
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Basement membrane (BM) formation is a key regulatory step in both normal and pathological vascularization. Laminins are key components of the vascular BM. Thus, we examined the functional role of the β2 and γ3 chain of laminin to retinal vascularization using knockout technology.
Retinas from PD 15 wild type (WT), β2-/-, γ3-/-, and β2-/-;γ3-/- mice were examined by conventional histology, IHC and EM. We used the following markers: GFAP for astrocytes; CD31 for endothelial cells; smooth muscle actin for pericytes; collagen IV, nidogen, and perlecan for the BM.
Laminin isoforms show a differential distribution on the retinal vasculature; the β2 and γ1 chains are ubiquitously expressed whereas the γ3 chain is found in only the arteries and capillaries. Next, we analyzed the phenotype of mice lacking one or both the β2 & γ3 genes. In the WT retina vascular development is largely complete by P15 and consists of a superficial arteries, veins and capillary network with an intermediary capillary network at the INL/IPL junction and a deep one in the OPL. Astrocytes are intimately associated with the superficial retinal vessels so that the astrocytes and vascular patterns are nearly identical. In the γ3 -/-there is increased branching of in the deep and intermediate capillary networks; however, the superficial and retinal vessels and astrocyte distribution is unaltered. In β2-/- retina disruptions in the superficial retinal network and well as the intermediate and deep microvessels are evident. β2-/-;γ3-/- mice had the most profound defects; these mutants have a complete failure in the development of the ILM and the superficial vessels showed a significant degree of tortuosity; the vascularization was incomplete, i.e, the capillary bed covered only the central two thirds of the retina; the remaining retina was avascular. Both the intermediate and deeper microvessels were disrupted. Astrocyte distribution was disorganized and large areas of the retinal surface were devoid of astrocytes. A disorganized and persistent intravitreal vascular network (hyaloid) was also found.
These data demonstrate that the ILM is a critical for the normal vascular development; including the regression of hyaloid vessels and development retinal microvessels. We hypothesize that BM laminins serve as anchorage sites for astrocytes and Müller cells which regulate vascular development. These studies demonstrate that BM components play a critical role in the normal and pathophysiologic retinal angiogenesis.
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