title: VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy.
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-1α 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.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Murilo
authors.initials: M
authors.lastname: Rodrigues
authors.forename: Xiaoban
authors.initials: X
authors.lastname: Xin
authors.forename: Kathleen
authors.initials: K
authors.lastname: Jee
authors.forename: Savalan
authors.initials: S
authors.lastname: Babapoor-Farrokhran
authors.forename: Fabiana
authors.initials: F
authors.lastname: Kashiwabuchi
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Imran
authors.initials: I
authors.lastname: Bhutto
authors.forename: Syed Junaid
authors.initials: SJ
authors.lastname: Hassan
authors.forename: Yassine
authors.initials: Y
authors.lastname: Daoud
authors.forename: David
authors.initials: D
authors.lastname: Baranano
authors.forename: Sharon
authors.initials: S
authors.lastname: Solomon
authors.forename: Gerard
authors.initials: G
authors.lastname: Lutty
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Silvia
authors.initials: S
authors.lastname: Montaner
authors.forename: Akrit
authors.initials: A
authors.lastname: Sodhi
mesh_terms: D000818:Animals; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D004077:Digoxin / Q000494:pharmacology; D004789:Enzyme Activation; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000209:etiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D004077:Digoxin; D020778:Matrix Metalloproteinase 2