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R Castellon, S Caballero, HK Hamdi, AM Aoki, MC Kenney, MB Grant, AV Ljubimov; Effects of Tenascin-C on the Angiogenic Potential of Retinal Endothelial Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1328.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Tenascin-C (TN-C) is an extracellular matrix protein expressed in embryogenesis and in adult tissues undergoing remodeling and healing. We previously reported that TN-C was upregulated in diabetic retinopathy (DR) human retinas. However, its precise role remained elusive. We hypothesized that TN-C promotes the angiogenic phenotype. Our purpose was to examine TN-C production by retinal endothelial cells (REC) in response to growth factors (GFs) known to be upregulated in DR, as well as the effects of TN-C +/- GFs on various in vitro angiogenic assays. Methods: Bovine and human REC were cultured on plastic and on reconstituted basement membrane matrix (Matrigel). TN-C production, capillary-like tube formation, secondary sprouting, cell migration, survival and proliferation were measured after treatment with combinations of angiogenic growth factors +/- TN-C. The involvement of TN-C integrin receptors on TN-C action was investigated using specific blocking antibodies. Results: TN-C delayed tube collapse of REC on Matrigel in a dose- and time-dependent manner. It also decreased tube collapse induced by serum deprivation, 30 mM glucose and 0.1 nM TGF-ß by 50%, 35% and 85%, with similar effects on REC growing on plastic. This indicates that TN-C exerts some survival effects. TN-C also increased secondary sprouting, REC proliferation, migration and tube branching. αVß3 integrin was important for TN-C action since a blocking antibody to this integrin decreased tube length, network complexity and secondary sprouting by 50%, 35% and 100%. Antibodies against αVß6, αVß5, and α9ß1 integrins had little or no effect. Immunocytochemistry showed that GFs known to be upregulated in DR retinas increased TN-C deposition in an additive or synergistic manner, which may explain why DR cells have higher basal levels of TN-C. Conclusion: TN-C was overexpressed in diabetic and DR REC cultures and was upregulated by GF combinations. TN-C enhanced the angiogenic potential of REC as measured by a variety of in vitro assays. The data suggest that TN-C may act as a pro-angiogenic mediator in DR and other pathological conditions and provide possible avenues for future therapeutic intervention.
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