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Julia A Staverosky, Ted S Acott, Janice A Vranka; Integrin α7-β1 heterodimer as a mechanosensor in the trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4725.
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Increasing intraccular pressure (IOP) is a distinct marker of glaucoma progression and decreasing IOP slows disease progression. The trabecular meshwork (TM) is responsible for maintaining homeostatic IOP. However, the specific molecular regulators of IPP have yet to be determined. The integrin α7-β1 heterodimer binds laminin and acts as a mechanosensor in muscle tissue. We previously identified that integrin α7 is elevated in high flow (HF) areas of the TM under 2X perfusion challenge compared to the HF areas of eyes perfused at 1X pressure. Here we confirm the presence of integrin α7 in the TM and investigate its role in sensing extracellular meshwork (ECM) changes and stretch as well as its ability to activate downstream signaling molecules in primary human TM cells (hTM).
Human donor eyes were perfused at either physiological pressure or 2X pressure challenge. TM was frontaly sectioned for immunofluorescences labeling and confocal imaging. Primary hTM cell lines were isolated from donor eyes and maintained up to 5 passages. Multiple (>5) independent cell lines were used for analysis. Cell lysates were used to immunoprecipitate integrin α7 or integrin β1 followed by western blot. Cells were plated on laminin and/or subjected to stretch, followed by lysis and western blot analysis of Akt, Erk, p38 and JNK signaling pathways.
Integrin α7 localizes to the juxtacanalicular tissue (JCT) of the TM in tissue. Integrin α7 binds integrin β1 and this heterodimer is activated in response to stretch and/or laminin binding. The primary pathway activated in response to stretch or laminin binding is the Akt pathway. The activity of JNK, p38 and Erk was broadly unaffected by stretch or laminin binding.
The integrin α7-β1 heterodimer is expressed in the TM and acts as a mechanosensor in hTM cells. Akt is the primary pathway activated in response to activation of the integrin α7-β1 heterodimer. We postulate that this heterodimer may be involved in sensing and adjusting to the elevated pressure in the TM in a similar manner to its ability to respond to mechanical stress in muscle tissue.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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