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Kay Beharry, Charles Cai, Poonam Sharma, Gloria Valencia, Douglas Lazzaro, Jacob Aranda; Retinal Protease and Collagen Responses to Increasing Numbers of Intermittent Hypoxia During Hyperoxia in a Rat Model for Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5568.
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The extracellular matrix (ECM) acts as an important protective barrier that restricts pathologic angiogenesis. Various proteases, such as plasmin and matrix metalloproteinases (MMPs), can degrade the ECM and cleave VEGF thus increasing its gradient and triggering pathologic angiogenesis. Degradation of ECM and VEGF involves the plasminogen activator system (PAS) consisting of the plasminogen activators (urokinase-type, or uPA), plasminogen activator inhibitors 1 (PAI-1), and the receptor for uPA (uPAR) which activate MMPs. Using an established model for oxygen-induced retinopathy (OIR), we examined the hypothesis that increasing episodes of intermittent brief hypoxia during hyperoxia, activates the PAS and MMPs and decreases collagen in the retina.
At birth (P0), neonatal rat pups were randomly assigned to 2, 4, 6, 8, 10, or 12 hyperoxia (50% O2)/hypoxia (12% O2) cycles from P0-P14 (14DO2). Pups were studied at P14 to determine immediate effects, or placed in room air (RA) until P21 (P21-14DO2). Type IV collagen, MMP-2, MMP-9, PAI-1, uPA, and uPAR were determined in the retina using ELISA.
Type IV collagen peaked with 6 cycles/day (1921.76±478.14 vs. 687.03±70.05, p<0.01) in the 14DO2 group vs. RA. This was coincident with elevations in MMP-2 (109.37±25.1 vs. 39.61±2.1, p<0.01), MMP-9 (1292.93±335.78 vs. 384.58±34.42, p<0.001), PAI-1 (527.52±118.99 vs. 178.67±16.5, p<0.01), uPA (5.79±1.42 vs. 1.8±0.14, p<0.01), and uPAR (460.92±105.54 vs. 151.09±16.32, p<0.001). Levels were decreased at 8 to 12 cycles/day. Only the animals exposed to 4 cycles/day had elevations in collagen and all proteases (p<0.05) post 7 days recovery in RA.
Six brief, intermittent hypoxic episodes during hyperoxia appear to be the number that generates maximum production of these proteases which likely work together to degrade the ECM and VEGF. In this model, the data imply that increased numbers of brief hypoxic episodes greater than 6 per day result in irreparable retinal ECM breakdown and VEGF cleavage ultimately leading to pathologic angiogenesis.
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