Opticin Exerts Its Anti-angiogenic Activity by Regulating Extracellular Matrix Adhesiveness*

Abstract

Background: Recently, we demonstrated that the glycoprotein opticin is anti-angiogenic. Here, the underpining mechanism is explored.

Results: By binding to collagen, opticin competitively inhibits integrin-mediated endothelial cell adhesion.

Conclusion: Opticin inhibits angiogenesis by weakening endothelial cell adhesion to the surrounding extracellular matrix.

Significance: Elucidating the regulatory mechanisms of angiogenesis is important for understanding pathology and drug discovery.

Abstract

Opticin is an extracellular matrix glycoprotein that we identified associated with the collagen network of the vitreous humor of the eye. Recently, we discovered that opticin possesses anti-angiogenic activity using a murine oxygen-induced retinopathy model: here, we investigate the underlying mechanism. Using an ex vivo chick chorioallantoic membrane assay, we show that opticin inhibits angiogenesis when stimulated by a range of growth factors. We show that it suppresses capillary morphogenesis, inhibits endothelial invasion, and promotes capillary network regression in three-dimensional matrices of collagen and Matrigel ^TM. We then show that opticin binds to collagen and thereby competitively inhibits endothelial cell interactions with collagen via α ₁β ₁ and α ₂β ₁ integrins, thereby preventing the strong adhesion that is required for proangiogenic signaling via these integrins.