The new study, published in Frontiers in Cellular Neuroscience, provides the first direct evidence that caveolae exist in optic nerve astrocytes and that their principal structural protein is strikingly concentrated in the glial lamina—the astrocyte-rich equivalent, in mice, of the human lamina cribrosa. This anatomical precision matters. In humans, the lamina cribrosa is a meshwork of connective tissue and elastic fibers through which the axons pass, while in mice the corresponding glial lamina is composed almost entirely of astrocytes. In both species, this is the principal site of axonal injury in primary open-angle glaucoma, and it is where the mechanical forces generated by intraocular pressure must be distributed and resisted to protect the nerve.

Caveolae are small, bulb-and-neck indentations of the plasma membrane, typically 50 to 100 nanometers in diameter, formed by the cooperative action of two protein families: the caveolins and the cavins. Caveolin-1 is indispensable—mice engineered to lack the protein lose their caveolae entirely—while Cavin-1 and its relatives form oligomeric complexes that stabilize the caveolar architecture. These structures act as membrane reservoirs that flatten out under acute mechanical stress, buffering sudden increases in membrane tension, and they also serve as signaling platforms that channel mechanical cues into intracellular pathways such as ERK and Akt activation. Until now, however, no one had systematically asked whether optic nerve astrocytes possess this machinery at all.

The Regensburg team, led by Andrea Dillinger and Rudolf Fuchshofer together with Michael Elliott, began by examining primary murine optic nerve astrocytes grown in culture. Scanning electron microscopy revealed classical caveolar structures on the cell surface, comparable in size and appearance to those of endothelial cells used as a positive control. Real-time PCR confirmed that the cells express Caveolin-1, Caveolin-2, and four of the five known Cavins, while Caveolin-3, which is restricted to muscle, was absent. Immunostaining verified that the two essential components, Caveolin-1 and Cavin-1, are abundantly present. In short, optic nerve astrocytes are fully equipped to build caveolae.

The in vivo picture was even more compelling. In eight-week-old wild-type mice, Caveolin-1 was found almost exclusively in the astrocytes of the glial lamina, with weaker signal in the prelaminar region and virtually none in the post-laminar optic nerve, where the faint staining that did appear appeared to derive from small blood vessels rather than astrocytes. This spatial restriction places the mechanosensitive apparatus precisely where glaucomatous damage begins, and it aligns with earlier genetic findings: genome-wide association studies have repeatedly linked variants between the CAV1 and CAV2 genes on chromosome 7 to both primary open-angle glaucoma and intraocular pressure.

The researchers then asked how the cells respond to glaucoma-relevant molecular signals. Two factors stand out in the diseased optic nerve head: CCN2/CTGF, a matricellular protein previously shown by the same group to drive extracellular matrix remodeling under biomechanical load, and TGF-β2, a fibrotic growth factor elevated in the aqueous humor and optic nerve head of glaucoma patients. Treating the astrocytes with either factor for 24 hours significantly increased both the mRNA and protein levels of Caveolin-1, and raised Cavin-1 protein as well. Conversely, silencing CCN2/CTGF with siRNA reduced Caveolin-1 mRNA expression. The relationship between CCN2/CTGF and the caveolar system thus appears bidirectional, hinting at a feedback loop in which the growth factor regulates its own upstream mechanosensor.

Perhaps the most striking experiments concerned stiffness. The team cultured astrocytes on substrata of defined elasticity—8 to 10 kilopascals, 50 to 60 kilopascals, and rigid glass at roughly 70 gigapascals—a range chosen to mirror real tissue mechanics. In a rabbit model, the Young’s modulus of the optic nerve head has been measured to rise from about 14 to 81 kilopascals as intraocular pressure climbs from 15 to 35 millimeters of mercury. On stiffer surfaces, the astrocytes produced significantly more Caveolin-1, and the protein’s distribution changed: instead of being spread evenly through the cytoplasm and along the membrane, it became punctate and accumulated near focal adhesions, partially overlapping with vinculin, a marker that confirmed the cells were actively sensing the mechanical properties of their environment.

Functional knockdown experiments added a provocative twist. When the researchers silenced Caveolin-1 in astrocytes grown on stiff substrata, they observed trends toward increased collagen IV production and an elevated ratio of phosphorylated to total focal adhesion kinase, suggesting that loss of Caveolin-1 may amplify extracellular matrix and adhesion signaling under mechanical load—possibly through altered actin cytoskeleton dynamics. Although the authors caution that these findings require replication with larger samples, they imply that Caveolin-1 could act as a brake on mechanotransduction, and that its dysregulation might tip astrocytes toward the reactive, matrix-remodeling state characteristic of glaucoma.

Finally, the team turned to the βB1-CTGF1 mouse, a transgenic glaucoma model in which CCN2/CTGF is overexpressed in the lens, producing elevated intraocular pressure and optic nerve damage. In these animals, Caveolin-1 mRNA was dramatically increased in the optic nerve head compared with wild-type littermates, and Caveolin-1 protein was elevated throughout the entire optic nerve. Because vascular endothelial cells also express abundant Caveolin-1, the authors note that some of the protein signal may originate from blood vessels, though the small endothelial fraction of the tissue makes astrocytes the likelier dominant source. Cell-type-specific analyses will be needed to settle the question.

What emerges is a coherent mechanistic hypothesis: elevated intraocular pressure stiffens the peripapillary sclera and the laminar extracellular matrix, astrocytes sense this change partly through caveolae, and glaucoma-associated factors such as CCN2/CTGF and TGF-β2 amplify the caveolar response, potentially feeding into YAP/TAZ-dependent transcriptional programs that drive further matrix remodeling. Whether the resulting Caveolin-1 upregulation ultimately protects the axons or accelerates their demise remains an open question—and an important one, given evidence from stroke and traumatic brain injury models that Caveolin-1 can be neuroprotective and support glial scar formation. Caveolin-1 knockout mice also show elevated intraocular pressure and impaired aqueous humor outflow, underscoring the protein’s multifaceted role in ocular physiology. If future work confirms that caveolae mediate the astrocyte’s perception of mechanical stress in the glial lamina, they could become an entirely new therapeutic target for a disease that currently can only be slowed, not stopped, by lowering eye pressure.

Subject of Research: Caveolin-1-mediated mechanosensing in optic nerve head astrocytes and its role in glaucoma

Article Title: Caveolin-1 defines astrocyte mechanobiology in the glial lamina of the optic nerve head

Article References: Hoffmann, A. K., Dlugosch, A., Geigenfeind, M. C., Seemann, A., Elliott, M. H., Fuchshofer, R., & Dillinger, A. E. (2026). Caveolin-1 defines astrocyte mechanobiology in the glial lamina of the optic nerve head. Frontiers in Cellular Neuroscience, 20, Article 1909639. https://doi.org/10.3389/fncel.2026.1909639

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1909639

Keywords: glaucoma, Caveolin-1, caveolae, astrocytes, optic nerve head, mechanobiology, intraocular pressure, CCN2/CTGF, TGF-beta2, extracellular matrix, glial lamina, mechanotransduction