Skip to main content
Top
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 8/2009

01-08-2009 | Pathology

Changes in choriocapillaris fenestration of rat eyes after intravitreal bevacizumab injection

Authors: Yukiko Shimomura, Akira Hirata, Shinichiro Ishikawa, Satoshi Okinami

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 8/2009

Login to get access

Abstract

Background

To examine the effects of anti-VEGF antibody (bevacizumab) on the number of fenestrations in rat choriocapillaris.

Methods

Twenty-four eyes from 24 male Wister rats were injected intravitreally with 0.125 mg of bevacizumab. The rats were perfusion fixated at 1, 3, 7, 14 or 28 days after injection. The surfaces of the choriocapillaris on the RPE side were observed using scanning electron microscopy. Four eyes treated with human IgG were used as controls. The area sieve plate and the number of fenestrations after the bevacizumab injection were measured and compared with controls.

Results

In the controls, the sieve plate area was 80.7% of the total choriocapillaris area. The number of fenestrations was 69.2 ± 0.2 /μm2 of the fenestrated area. While there were no changes in the fenestrated area for any of the time points after the bevacizumab treatment, the number of fenestrations was significantly reduced to 52.9 ± 4.4 at day 1, 55.6 ± 3.6 at day 3 and 53.6 ± 8.6 /μm2 of the luminal surface at day 7 (ANOVA, p < 0.05).

Conclusions

In this study, intravitreal bevacizumab injection reduced fenestration of the normal choriocapillaris. These results indicate there is a latent risk inherent with bevacizumab treatment of normal choriocapillaris.
Literature
1.
go back to reference Kvanta A, Algvere PV, Berglin L, Seregard S (1996) Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 37:1929–1934PubMed Kvanta A, Algvere PV, Berglin L, Seregard S (1996) Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 37:1929–1934PubMed
2.
go back to reference Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487. doi:10.1056/NEJM199412013312203 PubMedCrossRef Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487. doi:10.​1056/​NEJM199412013312​203 PubMedCrossRef
3.
go back to reference Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(Pt 6):2369–2379PubMed Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108(Pt 6):2369–2379PubMed
4.
go back to reference Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, Alitalo K, Kroon ME, Kijlstra A, van Hinsbergh VW, Schlingemann RO (1999) Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 155:421–428PubMed Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, Alitalo K, Kroon ME, Kijlstra A, van Hinsbergh VW, Schlingemann RO (1999) Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 155:421–428PubMed
5.
go back to reference Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342. doi:10.1056/NEJMoa032691 PubMedCrossRef Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342. doi:10.​1056/​NEJMoa032691 PubMedCrossRef
6.
go back to reference Heiduschka P, Fietz H, Hofmeister S, Schultheiss S, Mack AF, Peters S, Ziemssen F, Niggemann B, Julien S, Bartz-Schmidt KU, Schraermeyer U (2007) Penetration of bevacizumab through the retina after intravitreal injection in the monkey. Invest Ophthalmol Vis Sci 48:2814–2823. doi:10.1167/iovs.06–1171 PubMedCrossRef Heiduschka P, Fietz H, Hofmeister S, Schultheiss S, Mack AF, Peters S, Ziemssen F, Niggemann B, Julien S, Bartz-Schmidt KU, Schraermeyer U (2007) Penetration of bevacizumab through the retina after intravitreal injection in the monkey. Invest Ophthalmol Vis Sci 48:2814–2823. doi:10.​1167/​iovs.​06–1171 PubMedCrossRef
7.
go back to reference Rosenfeld PJ, Fung AE, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 36:336–339PubMed Rosenfeld PJ, Fung AE, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 36:336–339PubMed
9.
go back to reference Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331–335PubMed Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331–335PubMed
11.
12.
go back to reference Jonas JB, Harder B, Spandau UH, Kamppeter BA, Libondi T, Sauder G (2006) Bevacizumab for occult subfoveal neovascularization in age-related macular degeneration. Eur J Ophthalmol 16:774–775PubMed Jonas JB, Harder B, Spandau UH, Kamppeter BA, Libondi T, Sauder G (2006) Bevacizumab for occult subfoveal neovascularization in age-related macular degeneration. Eur J Ophthalmol 16:774–775PubMed
14.
go back to reference Korte GE, Reppucci V, Henkind P (1984) RPE destruction causes choriocapillary atrophy. Invest Ophthalmol Vis Sci 25:1135–1145PubMed Korte GE, Reppucci V, Henkind P (1984) RPE destruction causes choriocapillary atrophy. Invest Ophthalmol Vis Sci 25:1135–1145PubMed
16.
go back to reference Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR (2005) Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 167:1451–1459PubMed Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR (2005) Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 167:1451–1459PubMed
17.
go back to reference Krstić RV (1994) Human Microscopic Anatomy: An Atlas for Students of Medicine and Biology. Springer, New York Krstić RV (1994) Human Microscopic Anatomy: An Atlas for Students of Medicine and Biology. Springer, New York
19.
go back to reference Baluk P, Hirata A, Thurston G, Fujiwara T, Neal CR, Michel CC, McDonald DM (1997) Endothelial gaps: time course of formation and closure in inflamed venules of rats. Am J Physiol 272:L155–L170PubMed Baluk P, Hirata A, Thurston G, Fujiwara T, Neal CR, Michel CC, McDonald DM (1997) Endothelial gaps: time course of formation and closure in inflamed venules of rats. Am J Physiol 272:L155–L170PubMed
20.
go back to reference Hirata A, Baluk P, Fujiwara T, McDonald DM (1995) Location of focal silver staining at endothelial gaps in inflamed venules examined by scanning electron microscopy. Am J Physiol 269:L403–L418PubMed Hirata A, Baluk P, Fujiwara T, McDonald DM (1995) Location of focal silver staining at endothelial gaps in inflamed venules examined by scanning electron microscopy. Am J Physiol 269:L403–L418PubMed
21.
go back to reference Korte GE, Gerszberg T, Pua F, Henkind P (1986) Choriocapillaris atrophy after experimental destruction of the retinal pigment epithelium in the rat. A study in thin sections and vascular casts. Acta Anat (Basel) 127:171–175. doi:10.1159/000146277 CrossRef Korte GE, Gerszberg T, Pua F, Henkind P (1986) Choriocapillaris atrophy after experimental destruction of the retinal pigment epithelium in the rat. A study in thin sections and vascular casts. Acta Anat (Basel) 127:171–175. doi:10.​1159/​000146277 CrossRef
22.
go back to reference Leonard DS, Zhang XG, Panozzo G, Sugino IK, Zarbin MA (1997) Clinicopathologic correlation of localized retinal pigment epithelium debridement. Invest Ophthalmol Vis Sci 38:1094–1109PubMed Leonard DS, Zhang XG, Panozzo G, Sugino IK, Zarbin MA (1997) Clinicopathologic correlation of localized retinal pigment epithelium debridement. Invest Ophthalmol Vis Sci 38:1094–1109PubMed
23.
go back to reference Ioannidou S, Deinhardt K, Miotla J, Bradley J, Cheung E, Samuelsson S, Ng Y, Shima DT (2006) An in vitro assay reveals a role for the diaphragm protein PV-1 in endothelial fenestra morphogenesis. Proc Natl Acad Sci USA 103:16770–16775. doi:10.1073/pnas.0603501103 PubMedCrossRef Ioannidou S, Deinhardt K, Miotla J, Bradley J, Cheung E, Samuelsson S, Ng Y, Shima DT (2006) An in vitro assay reveals a role for the diaphragm protein PV-1 in endothelial fenestra morphogenesis. Proc Natl Acad Sci USA 103:16770–16775. doi:10.​1073/​pnas.​0603501103 PubMedCrossRef
24.
go back to reference Bock F, Onderka J, Dietrich T, Bachmann B, Kruse FE, Paschke M, Zahn G, Cursiefen C (2007) Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci 48:2545–2552. doi:10.1167/iovs.06–0570 PubMedCrossRef Bock F, Onderka J, Dietrich T, Bachmann B, Kruse FE, Paschke M, Zahn G, Cursiefen C (2007) Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci 48:2545–2552. doi:10.​1167/​iovs.​06–0570 PubMedCrossRef
26.
27.
28.
go back to reference Lu F, Adelman RA (2009) Are intravitreal bevacizumab and ranibizumab effective in a rat model of choroidal neovascularization? Graefes Arch Clin Exp Ophthalmol 247(2):171–177PubMedCrossRef Lu F, Adelman RA (2009) Are intravitreal bevacizumab and ranibizumab effective in a rat model of choroidal neovascularization? Graefes Arch Clin Exp Ophthalmol 247(2):171–177PubMedCrossRef
Metadata
Title
Changes in choriocapillaris fenestration of rat eyes after intravitreal bevacizumab injection
Authors
Yukiko Shimomura
Akira Hirata
Shinichiro Ishikawa
Satoshi Okinami
Publication date
01-08-2009
Publisher
Springer-Verlag
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 8/2009
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-009-1054-1

Other articles of this Issue 8/2009

Graefe's Archive for Clinical and Experimental Ophthalmology 8/2009 Go to the issue