How fibronectin fibrillogenesis can regulate aqueous humor outflow
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Purpose: Resistance to aqueous humor outflow across the trabecular meshwork (TM) is a dynamic process; the composition of the extracellular matrix (ECM) in the TM plays a role in regulating this resistance. Here, we discuss how the ECM protein fibronectin and its fibrillogenesis can contribute to the regulation of aqueous humor outflow.
Methods: The function of fibronectin has been studied using a variety of molecular and cellular approaches as well as animal models.
Results: Increased amounts of fibronectin in the TM have been found in aging and glaucomatous patients,
implicating a role for fibronectin in glaucoma. Fibronectin is a dimeric modular glycoprotein that can be alternatively spliced to generate 20 isoforms with different signaling functions. The EDA+ isoform which is
associated with causing a myofibroblast-like phenotype is expressed in the TM and can be upregulated by TGFβ,
a growth factor that is often elevated in aqueous humor of primary open-angle glaucoma patients. Fibronectin
typically exists as a fibril. Stretching of fibronectin fibrils by mechanical or cell contractile events exposes
cryptic binding interactions with other ECM proteins or TM cell receptors such as integrins and syndecans. The
newly exposed interactions can affect ECM assembly and elasticity, growth factor release, and matrix remodeling, all processes that can affect the ability of the TM to regulate IOP. Finally, although the active form of fibronectin is a fibril, degradation of fibronectin can result in the release of biologically active fragments that can affect TM function.
Conclusions: The role of fibronectin fibrillogenesis in the TM is multifactorial. Alternative splicing, matrix assembly, expression levels and turnover of fibronectin can affect how the TM responds to fluctuations in IOP, and dysregulation at any step can lead to a pathological state and the development of glaucoma.
Glaucoma Research 2018-2020, pp. 49-67 #4
Edited by: John R. Samples and Paul A. Knepper
© Kugler Publications, Amsterdam, The Netherlands
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