Hypoxic retinal Müller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4

Xiaoban Xin, Murilo Rodrigues, Mahaa Umapathi, Fabiana Kashiwabuchi, Tao Ma, Savalan Babapoor-Farrokhran, Shuang Wang, Jiadi Hu, Imran Bhutto, Derek S. Welsbie, Elia J Duh, James Handa, Charles G Eberhart, Gerard Anthony Lutty, Gregg L Semenza, Silvia Montaner, Akrit Sodhi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number36
DOIs
StatePublished - Sep 3 2013

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Hypoxia-Inducible Factor 1
Macular Edema
Capillary Permeability
Up-Regulation
Vascular Endothelial Growth Factor A
Permeability
Retina
Cytokines
Therapeutics
Papilledema
Eye Diseases
Digoxin
Ischemia
Endothelial Cells
angiopoietin 4
Oxygen
Gene Expression

Keywords

  • Angiogenesis
  • Diabetes
  • Retinal vein occlusion
  • Transcription factor

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Hypoxic retinal Müller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4. / Xin, Xiaoban; Rodrigues, Murilo; Umapathi, Mahaa; Kashiwabuchi, Fabiana; Ma, Tao; Babapoor-Farrokhran, Savalan; Wang, Shuang; Hu, Jiadi; Bhutto, Imran; Welsbie, Derek S.; Duh, Elia J; Handa, James; Eberhart, Charles G; Lutty, Gerard Anthony; Semenza, Gregg L; Montaner, Silvia; Sodhi, Akrit.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 36, 03.09.2013.

Research output: Contribution to journalArticle

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abstract = "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 M{\"u}ller 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, M{\"u}ller 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 M{\"u}ller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic M{\"u}ller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic M{\"u}ller 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.",
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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

AU - Eberhart, Charles G

AU - Lutty, Gerard Anthony

AU - Semenza, Gregg L

AU - Montaner, Silvia

AU - Sodhi, Akrit

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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.

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