Retinal vascular leakage occurring in GABA Rho-1 subunit deficient mice.
Recent studies demonstrate that GABAergic activity elicits relaxation of retinal arterioles leading to an increase in blood flow. It has also been found that GABAnergic activity in the retina of mice with diabetic retinopathy is suppressed. In this study, we provide further evidence that lack of GABAergic activity significantly alters vasculature development as well as the hypoxia-induced angiogenic response. Using GABA(C) receptor rho(1) subunit-knockout mice (rho-1(-/-)), our results demonstrate that in hypoxia-induced retinas a severe vascular leakage occurred in 2 week-old rho-1(-/-) mice compared with their wildtype counterparts. In addition, our results also showed that all of the rho-1(-/-) mice developed significant retinal vascular leakages by 48 weeks-of-age. Microarray and real-time PCR experiments revealed a unique angiogenesis-related gene expression pattern. This suggests that retinal vascular disorders of rho-1(-/-) mice results from significant up-regulation of angiogenic genes and concomitant down-regulation of anti-angiogenic genes. The study results are consistent with the pathological changes of the retinal vascular leakage seen in diabetic retinopathy. Our data indicate that the GABA(C) rho(1) subunit plays a role in maintaining both homeostasis and balance of retinal neurotransmitter function. Knockout of the retinal GABA(C) rho(1)-subunit leads to changes in vascular permeability similar to the pathological changes induced by retinal hypoxic conditions.
Zheng
Wei
W
Division of Molecular Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, CA 90502, USA.
Zhao
Xiaoping
X
Wang
Jie
J
Lu
Luo
L
D020533:Angiogenesis Inhibitors / Q000235:genetics; D042501:Angiogenic Proteins / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001813:Blood-Retinal Barrier; D002199:Capillary Permeability; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics; D000860:Hypoxia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000172:deficiency / Q000502:physiology*; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D017931:DNA Primers; C547869:Gabrr1 protein, mouse; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)