Ahmed M Abu El-Asrar1,2, Mohd Imtiaz Nawaz1, Ajmal Ahmad1, Mohammad Mairaj Siddiquei1, Eef Allegaert3,4, Priscilla W Gikandi1, Gert De Hertogh3,4, Ghislain Opdenakker4,5. 1. Department of Ophthalmology, College of Medicine and Medical City, King Saud University, Riyadh, Saudi Arabia. 2. Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 3. Laboratory of Histochemistry and Cytochemistry, University of Leuven (KU Leuven), Leuven, Belgium. 4. University Hospitals, UZ Gasthuisberg, Leuven, Belgium. 5. Department of Microbiology and Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven (KU Leuven), Leuven, Belgium.
Abstract
Purpose: Inflammation, angiogenesis and fibrosis are pathological hallmarks of proliferative diabetic retinopathy (PDR). The CD146/sCD146 pathway displays proinflammatory and proangiogenic properties. We investigated the role of this pathway in the pathophysiology of PDR. Methods: Vitreous samples from 41 PDR and 27 nondiabetic patients, epiretinal fibrovascular membranes from 18 PDR patients, rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy analysis. Blood-retinal barrier breakdown was assessed with fluorescein isothiocyanate-conjugated dextran. Results: sCD146 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic patients. In epiretinal membranes, immunohistochemical analysis revealed CD146 expression in leukocytes, vascular endothelial cells and myofibroblasts. Significant positive correlations were detected between numbers of blood vessels expressing CD31, reflecting angiogenic activity of PDR, and numbers of blood vessels and stromal cells expressing CD146. Western blot analysis showed significant increase of CD146 in diabetic rat retinas. sCD146 induced upregulation of phospho-ERK1/2, NF-κB , VEGF and MMP-9 in Müller cells. The hypoxia mimetic agent cobalt chloride, VEGF and TNF-α induced upregulation of sCD146 in HRMECs. The MMP inhibitor ONO-4817 attenuated TNF-α-induced upregulation of sCD146 in HRMECs. Intravitreal administration of sCD146 in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, intercellular adhesion molecule-1 and VEGF in the retina. sCD146 induced migration of HRMECs. Conclusions: These results suggest that the CD146/sCD146 pathway is involved in the initiation and progression of PDR.
Purpose: Inflammation, angiogenesis and fibrosis are pathological hallmarks of proliferative diabetic retinopathy (PDR). The CD146/sCD146 pathway displays proinflammatory and proangiogenic properties. We investigated the role of this pathway in the pathophysiology of PDR. Methods: Vitreous samples from 41 PDR and 27 nondiabetic patients, epiretinal fibrovascular membranes from 18 PDR patients, rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy analysis. Blood-retinal barrier breakdown was assessed with fluorescein isothiocyanate-conjugated dextran. Results:sCD146 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic patients. In epiretinal membranes, immunohistochemical analysis revealed CD146 expression in leukocytes, vascular endothelial cells and myofibroblasts. Significant positive correlations were detected between numbers of blood vessels expressing CD31, reflecting angiogenic activity of PDR, and numbers of blood vessels and stromal cells expressing CD146. Western blot analysis showed significant increase of CD146 in diabeticrat retinas. sCD146 induced upregulation of phospho-ERK1/2, NF-κB , VEGF and MMP-9 in Müller cells. The hypoxia mimetic agent cobalt chloride, VEGF and TNF-α induced upregulation of sCD146 in HRMECs. The MMP inhibitor ONO-4817 attenuated TNF-α-induced upregulation of sCD146 in HRMECs. Intravitreal administration of sCD146 in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, intercellular adhesion molecule-1 and VEGF in the retina. sCD146 induced migration of HRMECs. Conclusions: These results suggest that the CD146/sCD146 pathway is involved in the initiation and progression of PDR.
Authors: Ahmed M Abu El-Asrar; Ajmal Ahmad; Mohd Imtiaz Nawaz; Mohammad Mairaj Siddiquei; Alexandra De Zutter; Lotte Vanbrabant; Priscilla W Gikandi; Ghislain Opdenakker; Sofie Struyf Journal: Front Physiol Date: 2022-01-10 Impact factor: 4.566
Authors: Fabiana Mallone; Roberta Costi; Marco Marenco; Rocco Plateroti; Antonio Minni; Giuseppe Attanasio; Marco Artico; Alessandro Lambiase Journal: Int J Mol Sci Date: 2021-10-29 Impact factor: 5.923
Authors: Ahmed M Abu El-Asrar; Mohd Imtiaz Nawaz; Eef Allegaert; Mohammad Mairaj Siddiquei; Ajmal Ahmad; Priscilla Gikandi; Gert De Hertogh; Ghislain Opdenakker Journal: Molecules Date: 2022-09-14 Impact factor: 4.927