Hypoxia-inducible factor-dependent expression of angiopoietin-like 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia

Qianli Meng, Yaowu Qin, Monika Deshpande, Fabiana Kashiwabuchi, Murilo Rodrigues, Qiaozhi Lu, Hui Ren, Jennifer Hartt Elisseeff, Gregg L Semenza, Silvia V. Montaner, Akrit Sodhi

Research output: Contribution to journalArticle

Abstract

PURPOSE. Disappointing results from clinical studies assessing the efficacy of therapies targeting vascular endothelial growth factor (VEGF) for the treatment of pterygia suggest that other angiogenic mediators may also play a role in its development. We therefore explore the relative contribution of VEGF, hypoxia-inducible factor (HIF)-1α (the transcription factor that regulates VEGF expression in ocular neovascular disease), and a second HIF-regulated mediator, angiopoietin-like 4 (ANGPTL4), to the angiogenic phenotype of pterygia. METHODS. Expression of HIF-1α, VEGF, and ANGPTL4 were examined in surgically excised pterygia, and in immortalized human (ih) and primary rabbit (pr) conjunctival epithelial cells (CjECs). Endothelial cell (EC) tubule formation assays using media conditioned by ihCjECs in the presence or absence of inducers/inhibitors of HIF-1 or RNA interference (RNAi) targeting VEGF, ANGPTL4, or both were used to assess their relative contribution to the angiogenic potential of these cells. RESULTS. HIF-1α and VEGF expression were detected in 6/6 surgically excised pterygia and localized to CjECs. Accumulation of HIF-1α in was confirmed in ihCjECs and prCjECs, including stratified prCjECs grown on collagen vitrigel, and resulted in expression of VEGF and the promotion of EC tubule formation; the latter effect was partially blocked using RNAi targeting VEGF mRNA expression. We demonstrate expression of a second HIF-regulated angiogenic mediator, ANGPTL4, in CjECs in culture and in surgically excised pterygia. RNAi targeting ANGPTL4 inhibited EC tubule formation and was additive to RNAi targeting VEGF. CONCLUSIONS. Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia.

Original languageEnglish (US)
Pages (from-to)4514-4523
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number11
DOIs
StatePublished - Sep 1 2017

Fingerprint

Pterygium
Vascular Endothelial Growth Factor A
Epithelial Cells
Phenotype
Hypoxia-Inducible Factor 1
RNA Interference
Endothelial Cells
Hypoxia
angiopoietin 4
Eye Diseases
Angiogenesis Inducing Agents
Conditioned Culture Medium
Transcription Factors
Collagen
Therapeutics
Cell Culture Techniques
Rabbits

Keywords

  • Angiogenesis
  • Angiopoietin-like 4
  • Hypoxia-inducible factor
  • Pterygia
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Hypoxia-inducible factor-dependent expression of angiopoietin-like 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia. / Meng, Qianli; Qin, Yaowu; Deshpande, Monika; Kashiwabuchi, Fabiana; Rodrigues, Murilo; Lu, Qiaozhi; Ren, Hui; Elisseeff, Jennifer Hartt; Semenza, Gregg L; Montaner, Silvia V.; Sodhi, Akrit.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 11, 01.09.2017, p. 4514-4523.

Research output: Contribution to journalArticle

Meng, Qianli ; Qin, Yaowu ; Deshpande, Monika ; Kashiwabuchi, Fabiana ; Rodrigues, Murilo ; Lu, Qiaozhi ; Ren, Hui ; Elisseeff, Jennifer Hartt ; Semenza, Gregg L ; Montaner, Silvia V. ; Sodhi, Akrit. / Hypoxia-inducible factor-dependent expression of angiopoietin-like 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia. In: Investigative Ophthalmology and Visual Science. 2017 ; Vol. 58, No. 11. pp. 4514-4523.
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abstract = "PURPOSE. Disappointing results from clinical studies assessing the efficacy of therapies targeting vascular endothelial growth factor (VEGF) for the treatment of pterygia suggest that other angiogenic mediators may also play a role in its development. We therefore explore the relative contribution of VEGF, hypoxia-inducible factor (HIF)-1α (the transcription factor that regulates VEGF expression in ocular neovascular disease), and a second HIF-regulated mediator, angiopoietin-like 4 (ANGPTL4), to the angiogenic phenotype of pterygia. METHODS. Expression of HIF-1α, VEGF, and ANGPTL4 were examined in surgically excised pterygia, and in immortalized human (ih) and primary rabbit (pr) conjunctival epithelial cells (CjECs). Endothelial cell (EC) tubule formation assays using media conditioned by ihCjECs in the presence or absence of inducers/inhibitors of HIF-1 or RNA interference (RNAi) targeting VEGF, ANGPTL4, or both were used to assess their relative contribution to the angiogenic potential of these cells. RESULTS. HIF-1α and VEGF expression were detected in 6/6 surgically excised pterygia and localized to CjECs. Accumulation of HIF-1α in was confirmed in ihCjECs and prCjECs, including stratified prCjECs grown on collagen vitrigel, and resulted in expression of VEGF and the promotion of EC tubule formation; the latter effect was partially blocked using RNAi targeting VEGF mRNA expression. We demonstrate expression of a second HIF-regulated angiogenic mediator, ANGPTL4, in CjECs in culture and in surgically excised pterygia. RNAi targeting ANGPTL4 inhibited EC tubule formation and was additive to RNAi targeting VEGF. CONCLUSIONS. Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia.",
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T1 - Hypoxia-inducible factor-dependent expression of angiopoietin-like 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia

AU - Meng, Qianli

AU - Qin, Yaowu

AU - Deshpande, Monika

AU - Kashiwabuchi, Fabiana

AU - Rodrigues, Murilo

AU - Lu, Qiaozhi

AU - Ren, Hui

AU - Elisseeff, Jennifer Hartt

AU - Semenza, Gregg L

AU - Montaner, Silvia V.

AU - Sodhi, Akrit

PY - 2017/9/1

Y1 - 2017/9/1

N2 - PURPOSE. Disappointing results from clinical studies assessing the efficacy of therapies targeting vascular endothelial growth factor (VEGF) for the treatment of pterygia suggest that other angiogenic mediators may also play a role in its development. We therefore explore the relative contribution of VEGF, hypoxia-inducible factor (HIF)-1α (the transcription factor that regulates VEGF expression in ocular neovascular disease), and a second HIF-regulated mediator, angiopoietin-like 4 (ANGPTL4), to the angiogenic phenotype of pterygia. METHODS. Expression of HIF-1α, VEGF, and ANGPTL4 were examined in surgically excised pterygia, and in immortalized human (ih) and primary rabbit (pr) conjunctival epithelial cells (CjECs). Endothelial cell (EC) tubule formation assays using media conditioned by ihCjECs in the presence or absence of inducers/inhibitors of HIF-1 or RNA interference (RNAi) targeting VEGF, ANGPTL4, or both were used to assess their relative contribution to the angiogenic potential of these cells. RESULTS. HIF-1α and VEGF expression were detected in 6/6 surgically excised pterygia and localized to CjECs. Accumulation of HIF-1α in was confirmed in ihCjECs and prCjECs, including stratified prCjECs grown on collagen vitrigel, and resulted in expression of VEGF and the promotion of EC tubule formation; the latter effect was partially blocked using RNAi targeting VEGF mRNA expression. We demonstrate expression of a second HIF-regulated angiogenic mediator, ANGPTL4, in CjECs in culture and in surgically excised pterygia. RNAi targeting ANGPTL4 inhibited EC tubule formation and was additive to RNAi targeting VEGF. CONCLUSIONS. Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia.

AB - PURPOSE. Disappointing results from clinical studies assessing the efficacy of therapies targeting vascular endothelial growth factor (VEGF) for the treatment of pterygia suggest that other angiogenic mediators may also play a role in its development. We therefore explore the relative contribution of VEGF, hypoxia-inducible factor (HIF)-1α (the transcription factor that regulates VEGF expression in ocular neovascular disease), and a second HIF-regulated mediator, angiopoietin-like 4 (ANGPTL4), to the angiogenic phenotype of pterygia. METHODS. Expression of HIF-1α, VEGF, and ANGPTL4 were examined in surgically excised pterygia, and in immortalized human (ih) and primary rabbit (pr) conjunctival epithelial cells (CjECs). Endothelial cell (EC) tubule formation assays using media conditioned by ihCjECs in the presence or absence of inducers/inhibitors of HIF-1 or RNA interference (RNAi) targeting VEGF, ANGPTL4, or both were used to assess their relative contribution to the angiogenic potential of these cells. RESULTS. HIF-1α and VEGF expression were detected in 6/6 surgically excised pterygia and localized to CjECs. Accumulation of HIF-1α in was confirmed in ihCjECs and prCjECs, including stratified prCjECs grown on collagen vitrigel, and resulted in expression of VEGF and the promotion of EC tubule formation; the latter effect was partially blocked using RNAi targeting VEGF mRNA expression. We demonstrate expression of a second HIF-regulated angiogenic mediator, ANGPTL4, in CjECs in culture and in surgically excised pterygia. RNAi targeting ANGPTL4 inhibited EC tubule formation and was additive to RNAi targeting VEGF. CONCLUSIONS. Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia.

KW - Angiogenesis

KW - Angiopoietin-like 4

KW - Hypoxia-inducible factor

KW - Pterygia

KW - Vascular endothelial growth factor

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