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Roles of Thrombospondin-1 and -2 in Regulating Corneal and Iris Angiogenesis

¹From The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston Massachusetts; the ²Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington; and the ³Department of Pathology, Beth Israel Deaconess Medical Center, Research North, Boston, Massachusetts.

PURPOSE. Thrombospondin (TSP)-1 and -2 are important antiangiogenic factors thought to be involved in maintaining corneal avascularity (angiogenic privilege). This study was undertaken to investigate whether deficiencies of these factors altered developmental and inflammation-induced angiogenesis in the cornea and developmental angiogenesis of the iris of mice.

METHODS. Expression of TSP-1 and -2 mRNA and protein was assayed in cornea and iris stroma by RT-PCR and Western blot. Corneas and irides of TSP-1^-/-, TSP-2^-/-, and TSP-1,2^-/- mice aged 2, 3, and 6 months, and wild-type control mice, were analyzed for spontaneous angiogenesis biomicroscopically, histologically, and with CD31 immunohistochemistry. The mouse model of suture-induced, inflammatory corneal neovascularization was used to evaluate the lack of TSP-1,2 and both TSPs on induced-corneal angiogenesis. Seven days after intrastromal placement of three 11-0 sutures, vascularized areas were analyzed morphometrically on CD31-stained corneal flatmounts.

RESULTS. Corneas and irises from normal mouse eyes constitutively expressed TSP-1 and -2 mRNAs and proteins. Corneas of TSP-1^-/-, -2^-/-, and -1,2^-/- mice displayed no evidence of spontaneous developmental–postnatal angiogenesis, although irises of these mice contained significantly increased iris vessel density compared with wild-type animals (P < 0.01). One week after suturing, corneas of all TSP^-/- mice had significantly greater corneal angiogenesis than those of control mice (P < 0.05). TSP-1^-/- had a significantly greater effect on induced corneal neovascularization than did TSP-2^-/-, with the opposite being the case in developmental iris angiogenesis (P < 0.01).

CONCLUSIONS. Corneal avascularity during development is redundantly regulated, shown by the fact that lack of the antiangiogenic factors TSP-1 and/or -2 resulted in no spontaneous corneal angiogenesis. By contrast, TSP-1, more than TSP-2, helps to suppress inflammation-induced corneal angiogenesis postnatally, implying that angiogenic privilege in the cornea is actively maintained.

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