Caveolin-1 defines astrocyte mechanobiology in the glial lamina of the optic nerve head.

The optic nerve head is the principal site of retinal ganglion cell axonal injury in primary open angle glaucoma, where astrocyte mechanobiology and extracellular matrix remodeling are thought to play critical roles in disease progression. Caveolae, which are mechanosensitive plasma membrane invaginations formed by Caveolin and Cavin proteins, are key regulators of cellular responses to mechanical stress, yet their involvement in optic nerve head pathophysiology has not been defined. Here, we characterize the presence, regulation, and mechanobiological relevance of Caveolin and Cavin proteins in murine optic nerve astrocytes in vitro and in vivo. Primary optic nerve astrocytes exhibited classical caveolar structures and expressed Caveolin-1, Caveolin-2 and multiple Cavins. In vivo, Caveolin-1 is highly enriched in astrocytes of the glial lamina. Glaucoma-associated factors CCN2/CTGF and TGF-β2 significantly increased Caveolin-1 and Cavin-1 expression in optic nerve astrocytes, while CCN2/CTGF knockdown reduced Caveolin-1 expression. Increasing substratum stiffness enhanced Caveolin-1 expression and altered the subcellular localization of Caveolin-1. Furthermore, Caveolin-1 mRNA expression was increased in the optic nerve head of a glaucoma mouse model, while its protein levels were elevated in the entire optic nerve of the transgenic mice. Together, these findings identify caveolae and Caveolin-1 as mechanosensitive components of optic nerve astrocytes and suggest their involvement in biomechanical and molecular alterations of the glaucomatous optic nerve head. This work provides the first evidence linking astrocyte mechanobiology in the glial lamina to Caveolin-1, highlighting a potential novel contributor to glaucoma pathogenesis.