Chorioretinal Ischemia and Angiogenic Milieu Following Photodynamic Therapy

Purpose: To investigate the development of chorioretinal ischemia and expression of angiogenic factors following photodynamic therapy (PDT) in normal rat chorioretina. Materials and Methods: Pimonidazole (hypoxia marker) was intraperitoneally administrated 15 min before PDT (to identify the intra-PDT ischemia) and at 10 days and 20 days after PDT (to identify post-PDT ischemia) in 14 Brown-Norway rats (4 rats at each point and 2 rats serving as controls). After enucleation and cryosection at each point, immunohistofluorescent (IHF) staining for pimonidazole was evaluated with confocal scanning microscopy. In another 14 rats, the expression of angiogenic factors following PDT was demonstrated in PDT-irradiated normal chorioretina. Four rats were randomly selected at 3, 7, and 14 days following PDT with 2 rats serving as controls (verteporfin-/laser-). The expressions of vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), and hypoxia-inducible factor (HIF)-1a were evaluated at each point. Diode laser (689 nm, 25 J/cm(2)) was irradiated before verteporfin infusion in the left eye (verteporfin-/laser+) and after infusion in the right eye (verteporfin+/laser+) in each experiment. Results: Intensity of pimonidazole uptake increased during PDT and at 10 and 20 days following PDT. The intensity of pimonidazole was the most pronounced immediately after PDT irradiation, but VEGF expression was rarely detected immediately after PDT. VEGF, IGF, and HIF-1a expression increased at 3 days and 7 days. At 14 days after PDT, the expression of VEGF was sustained, but that of IGF and HIF-1a was irregular. Conclusions: These results show that significant chorioretinal ischemia develops in the irradiated area following PDT and that the ischemia is most pronounced during PDT irradiation. Along with post-PDT overexpression of angiogenic factors, this may be a mechanism contributing to PDT resistance or recurrence of chorioretinal neovascular lesions.Tatar O, 2007, RETINA-J RET VIT DIS, V27, P713Tatar O, 2006, AM J OPHTHALMOL, V142, P95, DOI 10.1016/j.ajo.2006.01.085Tatar O, 2006, ARCH OPHTHALMOL-CHIC, V124, P815*TAP STUD GROUP, 2006, GRAEFES ARCH CLIN EX, V244, P1132Chang TC, 2005, J BIOL CHEM, V280, P36567, DOI 10.1074/jbc.M504280200Greve MDJ, 2005, ARCH OPHTHALMOL-CHIC, V123, P448Grunwald JE, 2005, INVEST OPHTH VIS SCI, V46, P1033, DOI 10.1167/iovs.04-1050Ciulla TA, 2005, BRIT J OPHTHALMOL, V89, P113, DOI 10.1136/bjo.2004.043075Jiang F, 2004, PHOTOCHEM PHOTOBIOL, V79, P494Tano Y, 2003, AM J OPHTHALMOL, V136, P1049, DOI 10.1016/S0002-9394(03)00576-2Huang Z, 2003, PHOTOCHEM PHOTOBIOL, V78, P496Schmidt-Erfurth U, 2003, INVEST OPHTH VIS SCI, V44, P4473, DOI 10.1167/iovs.02-1115Lambooij AC, 2003, INVEST OPHTH VIS SCI, V44, P2192, DOI 10.1167/iovs.02-0410Schlotzer-Schrehardt U, 2002, GRAEF ARCH CLIN EXP, V240, P748, DOI 10.1007/s00417-002-0517-4Zacks DN, 2002, INVEST OPHTH VIS SCI, V43, P2384Liu LX, 2002, BIOCHEM BIOPH RES CO, V291, P908, DOI 10.1006/bbrc.2002.6551Schmidt-Erfurth U, 2002, INVEST OPHTH VIS SCI, V43, P830Chen B, 2001, INT J ONCOL, V18, P1279Arnold J, 2001, AM J OPHTHALMOL, V131, P541Ferrario A, 2000, CANCER RES, V60, P4066Bressler NM, 1999, ARCH OPHTHALMOL-CHIC, V117, P1329Husain D, 1999, INVEST OPHTH VIS SCI, V40, P2322Engbrecht BW, 1999, CANCER RES, V59, P4334Huang LE, 1998, P NATL ACAD SCI USA, V95, P7987Arteel GE, 1998, EUR J BIOCHEM, V253, P743Sitnik TM, 1998, BRIT J CANCER, V77, P1386Grunwald JE, 1998, INVEST OPHTH VIS SCI, V39, P385Gilpin DA, 1996, BURNS, V22, P607Starita C, 1996, EXP EYE RES, V62, P565Lopez PF, 1996, INVEST OPHTH VIS SCI, V37, P855ARTEEL GE, 1995, BRIT J CANCER, V72, P889VINGERLING JR, 1995, OPHTHALMOLOGY, V102, P205KLEIN R, 1992, OPHTHALMOLOGY, V99, P933FINGAR VH, 1988, CANCER RES, V48, P3350FERRIS FL, 1984, ARCH OPHTHALMOL-CHIC, V102, P1640