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X. Gasull, E. E. Syriani, E. Abad, G. Cuesto, J. Pintor, M. Morales; PDGF and the Rac1 Pathway Modulate Aqueous Humor Outflow and Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3712. doi: https://doi.org/.
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It is well known that the small GTPase RhoA modulates the actin cytoskeleton and cellular contractility in the trabecular meshwork (TM). Several substances known to contract the TM, reduce outflow facility, while cellular relaxation is commonly associated to the opposite effect. In this sense, inhibitors of the RhoA pathway are being developed as antiglaucomatous drugs. Here we investigate the role of platelet-derived growth factor, a known activator of the Rac1 pathway, in cell cytoskeleton, outflow facility and intraocular pressure (IOP).
Effects of PDGF on actin cytoskeleton, Rac1 and AKT activation were tested in bovine TM cells in culture. Rac1 and AKT/P-AKT activation were assessed by western blot. Trabecular outflow facility was measured in bovine perfused anterior segments. Changes on IOP were measured after topical application in the cornea of rabbit eyes by means of a Tonopen for a period up to 8 hours.
In TM cells, PDGF (10 ng/ml) activated Rac1 via AKT and induced actin cytoskeleton rearrangement with lamellipodia formation. In this sense, lamellipodia formation in TM cells was prevented by NSC23766, a Rac1 inhibitor and LY29004, a PI3K inhibitor. In perfused anterior segments, PDGF (100 ng/ml) increased trabecular outflow facility by 26%. In vivo, when topically applied to rabbit’s corneas, PDGF induced a 20% decrease in IOP (100 ng/ml). This reduction was concentration-dependent and presented an EC50 value of 2.7 nM.
PDGF, by activating the Rac1 pathway, induces cytoskeletal changes in TM cells that enhance outflow facility. Decreased IOP after PDGF application is likely due to the facilitation of AH outflow. Rac1 pathway activator appears a positive modulator of outflow facility and an interesting target to decrease IOP after ocular hypertension.
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