VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy

Murilo Rodrigues, Xiaoban Xin, Kathleen Jee, Savalan Babapoor-Farrokhran, Fabiana Kashiwabuchi, Tao Ma, Imran Bhutto, Syed Junaid Hassan, Yassine Daoud, David Baranano, Sharon Solomon, Gerard Anthony Lutty, Gregg L Semenza, Silvia Montaner, Akrit Sodhi

Research output: Contribution to journalArticle

Abstract

In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloproteinases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1a in Müller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic Müller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.

Original languageEnglish (US)
Pages (from-to)3863-3873
Number of pages11
JournalDiabetes
Volume62
Issue number11
DOIs
StatePublished - Nov 2013

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Retinal Neovascularization
Matrix Metalloproteinase 2
Diabetic Retinopathy
Vascular Endothelial Growth Factor A
Endothelial Cells
Matrix Metalloproteinases
Proteolysis
Ischemia
Therapeutics
Eye Diseases
Light Coagulation
Angiogenesis Inducing Agents

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. / Rodrigues, Murilo; Xin, Xiaoban; Jee, Kathleen; Babapoor-Farrokhran, Savalan; Kashiwabuchi, Fabiana; Ma, Tao; Bhutto, Imran; Hassan, Syed Junaid; Daoud, Yassine; Baranano, David; Solomon, Sharon; Lutty, Gerard Anthony; Semenza, Gregg L; Montaner, Silvia; Sodhi, Akrit.

In: Diabetes, Vol. 62, No. 11, 11.2013, p. 3863-3873.

Research output: Contribution to journalArticle

Rodrigues, Murilo ; Xin, Xiaoban ; Jee, Kathleen ; Babapoor-Farrokhran, Savalan ; Kashiwabuchi, Fabiana ; Ma, Tao ; Bhutto, Imran ; Hassan, Syed Junaid ; Daoud, Yassine ; Baranano, David ; Solomon, Sharon ; Lutty, Gerard Anthony ; Semenza, Gregg L ; Montaner, Silvia ; Sodhi, Akrit. / VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. In: Diabetes. 2013 ; Vol. 62, No. 11. pp. 3863-3873.
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abstract = "In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloproteinases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1a in M{\"u}ller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic M{\"u}ller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.",
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AU - Rodrigues, Murilo

AU - Xin, Xiaoban

AU - Jee, Kathleen

AU - Babapoor-Farrokhran, Savalan

AU - Kashiwabuchi, Fabiana

AU - Ma, Tao

AU - Bhutto, Imran

AU - Hassan, Syed Junaid

AU - Daoud, Yassine

AU - Baranano, David

AU - Solomon, Sharon

AU - Lutty, Gerard Anthony

AU - Semenza, Gregg L

AU - Montaner, Silvia

AU - Sodhi, Akrit

PY - 2013/11

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AB - In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloproteinases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1a in Müller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic Müller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.

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