June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Bone morphogenetic protein 2 contributes to diabetes-induced extracellular matrix deposition and apoptosis in retinal microvasculature
Author Affiliations & Notes
  • Khaled Elmasry
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Ahmed S Ibrahim
    Department of Ophthalmology and Anatomical Sciences, Wayne State University, Detroit, Michigan, United States
    Department of Pharmacology, Wayne State University, Detroit, Michigan, United States
  • Mohamed Moustafa
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Yunjoo Shin
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Kathereen Albishara
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Mohamed Al-Sayed Al-Shabrawey
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Footnotes
    Commercial Relationships   Khaled Elmasry None; Ahmed S Ibrahim None; Mohamed Moustafa None; Yunjoo Shin None; Kathereen Albishara None; Mohamed Al-Shabrawey None
  • Footnotes
    Support  NIH Grant 7R01EY030054-03
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3597 – A0052. doi:
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    • Get Citation

      Khaled Elmasry, Ahmed S Ibrahim, Mohamed Moustafa, Yunjoo Shin, Kathereen Albishara, Mohamed Al-Sayed Al-Shabrawey; Bone morphogenetic protein 2 contributes to diabetes-induced extracellular matrix deposition and apoptosis in retinal microvasculature. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3597 – A0052.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Diabetic retinopathy (DR) is the most common cause of blindness in the middle age group. Therapies targeting early stages of DR are urgently needed. One of the earliest changes in DR is endothelial basement membrane thickening, via extracellular matrix (ECM) deposition. The current study tests the hypothesis that bone morphogenetic protein 2 (BMP2) participates in ECM deposition in early DR, representing a possible therapeutic target.

Methods : We evaluated levels of fibronectin in human retinal endothelial cells (HRECs) treated with BMP2 or High glucose (HG) in presence or absence of BMP2 or VEGF inhibitors (LDN1, 100 nM and SU5416, 10µM respectively). We injected wild type mice intravitreally with BMP2 (50ng/ml) or its vehicle (n=4/group). One week later, Western Blot (WB) analysis of retinal fibronectin was performed. Injected mice were also used to prepare flat-mounted retinas co-stained with Isolectin B4 and fibronectin. Conditional endothelial knockout (cKo) mouse model was generated, with deleted BMP receptors (ALK2/3) in endothelial cells. ALK2/3 cKo mice and their littermate controls with/without diabetes of 8 weeks duration (n=3-4 /group) were evaluated with fluorescein angiogram (FA) followed by retinal RT-PCR for inflammatory, apoptotic and fibrotic markers. The results are expressed as means ± SEM. One-way ANOVA or two-tailed t test were used for statistical analysis. Results were considered significant for p <0.05.

Results : BMP2 significantly upregulated fibronectin in HRECs (p=0.012). Inhibition of BMP signaling but not VEGF significantly attenuated HG-induced fibronectin production (p=0.0013). BMP2 injected mice showed a dense membrane of fibronectin obscuring retinal vessels in flat mounted retinas and also a significant increase of fibronectin levels (p= 0.0013) compared to the vehicle injected eyes evaluated by WB. Apoptotic markers; caspase-3 and Fas Ligand mRNA levels were significantly increased with diabetes (p< 0.05); however, Fas ligand levels were restored to normal in retinas of diabetic ALK2/3 cKo mice. FA didn’t detect any significant vascular changes in diabetic ALK2/3 cKo mice.

Conclusions : BMP2 induces ECM deposition and promote apoptosis which may contribute to microvascular dysfunction and permeability during DR. BMP2 could be a possible therapeutic target for early stage DR.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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