TY - JOUR
T1 - Hypoxic retinal Müller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4
AU - Xin, Xiaoban
AU - Rodrigues, Murilo
AU - Umapathi, Mahaa
AU - Kashiwabuchi, Fabiana
AU - Ma, Tao
AU - Babapoor-Farrokhran, Savalan
AU - Wang, Shuang
AU - Hu, Jiadi
AU - Bhutto, Imran
AU - Welsbie, Derek S.
AU - Duh, Elia J.
AU - Handa, James T.
AU - Eberhart, Charles G.
AU - Lutty, Gerard
AU - Semenza, Gregg L.
AU - Montaner, Silvia
AU - Sodhi, Akrit
PY - 2013/9/3
Y1 - 2013/9/3
N2 - Vision loss from ischemic retinopathies commonly results from the accumulation of fluid in the inner retina [macular edema (ME)]. Although the precise events that lead to the development of ME remain under debate, growing evidence supports a role for an ischemia-induced hyperpermeability state regulated, in part, by VEGF. Monthly treatment with anti-VEGF therapies is effective for the treatment of ME but results in a major improvement in vision in a minority of patients, underscoring the need to identify additional therapeutic targets. Using the oxygen-induced retinopathy mouse model for ischemic retinopathy, we provide evidence showing that hypoxic Müller cells promote vascular permeability by stabilizing hypoxia-inducible factor-1α (HIF-1α) and secreting angiogenic cytokines. Blocking HIF-1α translation with digoxin inhibits the promotion of endothelial cell permeability in vitro and retinal edema in vivo. Interestingly, Müller cells require HIF - but not VEGF - to promote vascular permeability, suggesting that other HIF-dependent factors may contribute to the development of ME. Using gene expression analysis, we identify angiopoietin-like 4 (ANGPTL4) as a cytokine up-regulated by HIF-1 in hypoxic Müller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic Müller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic Müller cells. Our results suggest that ANGPTL4 may play an important role in promoting vessel permeability in ischemic retinopathies and could be an important target for the treatment of ME.
AB - Vision loss from ischemic retinopathies commonly results from the accumulation of fluid in the inner retina [macular edema (ME)]. Although the precise events that lead to the development of ME remain under debate, growing evidence supports a role for an ischemia-induced hyperpermeability state regulated, in part, by VEGF. Monthly treatment with anti-VEGF therapies is effective for the treatment of ME but results in a major improvement in vision in a minority of patients, underscoring the need to identify additional therapeutic targets. Using the oxygen-induced retinopathy mouse model for ischemic retinopathy, we provide evidence showing that hypoxic Müller cells promote vascular permeability by stabilizing hypoxia-inducible factor-1α (HIF-1α) and secreting angiogenic cytokines. Blocking HIF-1α translation with digoxin inhibits the promotion of endothelial cell permeability in vitro and retinal edema in vivo. Interestingly, Müller cells require HIF - but not VEGF - to promote vascular permeability, suggesting that other HIF-dependent factors may contribute to the development of ME. Using gene expression analysis, we identify angiopoietin-like 4 (ANGPTL4) as a cytokine up-regulated by HIF-1 in hypoxic Müller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic Müller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic Müller cells. Our results suggest that ANGPTL4 may play an important role in promoting vessel permeability in ischemic retinopathies and could be an important target for the treatment of ME.
KW - Angiogenesis
KW - Diabetes
KW - Retinal vein occlusion
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=84883319645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883319645&partnerID=8YFLogxK
U2 - 10.1073/pnas.1217091110
DO - 10.1073/pnas.1217091110
M3 - Article
C2 - 23959876
AN - SCOPUS:84883319645
SN - 0027-8424
VL - 110
SP - E3425-E3434
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -