Effects of Platelet-Derived Growth Factor on Aqueous Humor Dynamics
Effects of Platelet-Derived Growth Factor on Aqueous Humor Dynamics
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DOI：
10.1167/iovs.08-2924
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发表时间：
2009-08-01
影响因子：
4.4
通讯作者：
Gasull, Xavier
中科院分区：
文献类型：
--
作者：
Syriani, Emilio;Cuesto, German;Gasull, Xavier
目的。众所周知，小梁网中的小GTP酶RhoA调节肌动蛋白细胞骨架和细胞收缩。已知的几种物质收缩TM减少流出设施，而细胞松弛通常与相反的效果有关。RhoA途径的抑制剂正在开发中，作为抗青光眼药物。在这里，作者研究了已知的rac1途径的激活物--血小板衍生生长因子(PDGF)在细胞骨架、流出通道和眼压(IOP)中的作用。方法：在培养的融合前和融合的牛TM细胞中检测了PDGF对肌动蛋白细胞骨架、rac1和AKT激活的影响。用Western印迹法检测细胞内Rac1和AKT/P-AKT的活性。在牛的前段灌流中测量小梁流出能力。结果：在TM细胞中，PDGF(10 ng/mL)通过AKT激活rac1，并诱导肌动蛋白细胞骨架重排，形成片状脂膜。从这个意义上讲，RAC1抑制剂NSC23766和PI3K抑制剂LY294002可以阻止TM细胞片状脂血症的形成。在灌流的前段，PDGF(100 ng/mL)使小梁流出能力增加26%。在体内，当局部应用于兔角膜时，PDGF诱导眼压下降20%(100 ng/mL)。这种减少是浓度依赖的，EC50值为2.7 nM。结论PDGF通过激活rac1通路，诱导TM细胞发生细胞骨架改变，从而增强流出的便利性。PDGF应用后眼压下降可能是由于促进房水流出所致。Rac1通路的激活似乎是流出设施的积极调节因素，也是降低高眼压后眼压的一个有趣的靶点。(投资眼科VS科学。网址：10.1167/iovs.08-2924
PURPOSE. It is well known that the small GTPase RhoA modulates actin cytoskeleton and cellular contractility in the trabecular meshwork (TM). Several substances known to contract the TM reduce outflow facility, whereas cellular relaxation is commonly associated with the opposite effect. Inhibitors of the RhoA pathway are under development as antiglaucoma drugs. Here the authors investigate the role of platelet-derived growth factor (PDGF), a known activator of the Rac1 pathway, in cell cytoskeleton, outflow facility, and intraocular pressure (IOP).METHODS. Effects of PDGF on actin cytoskeleton, Rac1, and AKT activation were tested in preconfluent and confluent bovine TM cells in culture. Rac1 and AKT/P-AKT activation were assessed by Western blot analysis. Trabecular outflow facility was measured in bovine perfused anterior segments. Changes in IOP were measured for up to 6 hours after topical application in the cornea of rabbit eyes by means of a contact tonometer.RESULTS. In TM cells, PDGF (10 ng/mL) activated Rac1 through 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 LY294002, a PI3K inhibitor. In perfused anterior segments, PDGF (100 ng/mL) increased trabecular outflow facility by 26%. In vivo, when topically applied to rabbit 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.CONCLUSIONS. PDGF, by activating the Rac1 pathway, induces cytoskeletal changes in TM cells that enhance outflow facility. Decreased IOP after PDGF application is likely caused by the facilitation of aqueous humor outflow. Rac1 pathway activation appears to be a positive modulator of outflow facility and an interesting target for decreasing IOP after ocular hypertension. (Invest Ophthalmol Vis Sci. 2009; 50: 3833-3839) DOI: 10.1167/iovs.08-2924