ArticleFrontiers in immunology2020
Bone Morphogenetic Protein-2 Induces Non-Canonical Inflammatory and Oxidative Pathways in Human Retinal Endothelial Cells.
Article in Frontiers in immunology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 17 citations in OpenAlex.
- Interleukin 27-induced photoreceptor survival is associated with suppression of a novel Muller glia subpopulation.Cell communication and signaling : CCS · 2026Article
- Development of targeted drugs for diabetic retinopathy using Mendelian randomized pharmacogenomics.Frontiers in endocrinology · 2025Article
- Mechanisms of Bone Morphogenetic Protein 2 in Respiratory Diseases.Current allergy and asthma reports · 2024Review
- Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: from the perspective of cellular and molecular components.Cell & bioscience · 2024Review
- TGF-β Signaling Pathways in the Development of Diabetic Retinopathy.International journal of molecular sciences · 2024Review
- Effects and potential mechanisms of exercise and physical activity on eye health and ocular diseases.Frontiers in medicine · 2024Review
- Article
- Formation and characterization of BMP2/GDF5 and BMP4/GDF5 heterodimers.BMC biology · 2023Article
- Evidence of vascular involvement in myopia: a review.Frontiers in medicine · 2023Review
- BMP2 inhibits cell proliferation by downregulating EZH2 in gastric cancer.Cell cycle (Georgetown, Tex.) · 2022Article
- Trimetazidine mitigates high glucose-induced retinal endothelial dysfunction by inhibiting PI3K/Akt/mTOR pathway-mediated autophagy.Bioengineered · 2022Article
- Bone Morphogenetic Proteins and Diabetic Retinopathy.Biomolecules · 2021Review
- Atypical p38 Signaling, Activation, and Implications for Disease.International journal of molecular sciences · 2021Review
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Authors and funding
10 authors at 6 institutions in 3 countries.
Funding
Abstract
The mechanisms of diabetic retinopathy (DR), are not yet fully understood. We previously demonstrated an upregulation of retinal bone morphogenetic protein-2 (BMP2) in experimental diabetes and in retinas of diabetic human subjects. The purpose of current study was to investigate the role of non-canonical inflammatory pathway in BMP2-induced retinal endothelial cell (REC) barrier dysfunction. For this purpose, we used RT-PCR and western blotting to evaluate the levels of BMP2 signaling components (BMP2, BMP4, BMP receptors), VEGF, phosphorylated p38 MAPK and NFκB, and oxidative stress markers in cultured human retinal endothelial cells (HRECs) subjected to BMP2 (50ng/ml) for up to 24 h. Also, effect of high glucose (HG, 30mM D-glucose) on the expression of BMP2 and its downstream genes was examined in HRECs. H2-DCF is a fluorogenic dye that measures the levels of cellular reactive oxygen species (ROS) was used to measure the pro-oxidative effect of BMP2. Moreover, we evaluated the effect of inhibiting p38 and VEGF signaling on BMP2-induced HRECs barrier dysfunction by measuring the trans-endothelial cell electrical resistance (TER) using electric cell-substrate impedance sensing (ECIS). We also tested the effect of HG on the integrity of HRECs barrier in the presence or absence of inhibitors of BMP2 signaling. Our data reveals that BMP2 and high glucose upregulates BMP components of the BMP signaling pathway (SMAD effectors, BMP receptors, and TGFβ ligand itself) and induces phosphorylation of p38 MAPK and NFκB with nuclear translocation of NFκB. Inhibition of p38 or NFκB attenuated BMP2-induced VEGF expression and barrier dysfunction in HRECs. Also, inhibition of VEGFR2 attenuated BMP2-induced barrier dysfunction. Moreover, BMP2 induces generation of ROS and endothelial nitric oxide synthase (eNOS) expression and activity in HRECs. Finally, HG upregulated BMP2 and its downstream genes (SMAD, BMP4, ALKs, and TGF-β) in HRECs and BMP2 inhibitors attenuated HG-induced HRECs barrier dysfunction. Our results suggest that in addition to the regular canonical SMAD signaling BMP2 induces non-canonical inflammatory pathway in HRECs
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