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Publications

Journal Article Research Support, Non-U.S. Gov't Epublish 9 citations

PubMed: 39851513 DOI: 10.3390/cells14020085

ADAMTS13 Improves Endothelial Function and Reduces Inflammation in Diabetic Retinopathy.

Cells 14(2)

Authors: Ahmed M Abu El-Asrar, Mohd I Nawaz, Ajmal Ahmad, Mairaj Siddiquei, Eef Allegaert, Lowie Adyns, Lotte Vanbrabant, Priscilla W Gikandi, Gert De Hertogh, Sofie Struyf, Ghislain Opdenakker

Affiliations

  • Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
  • Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
  • Laboratory of Histochemistry and Cytochemistry, University of Leuven, 3000 Leuven, Belgium.
  • University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium.
  • Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium.
  • Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium.

Abstract

The protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif member 13 (ADAMTS13), known to cleave only the von Willebrand factor (VWF), has powerful regulatory effects on microvascular platelet adhesion, thrombosis, inflammation, and endothelial dysfunction. We study the protection against diabetes-induced retinal injury in experimental rats by supplementation with recombinant ADAMTS13. We compare human epiretinal membranes and vitreous samples from nondiabetic subjects and patients with proliferative diabetic retinopathy (PDR) and extend in vitro analyses with the use of various immunodetection and spectrofluorimetric methods on rat retina and human retinal glial and endothelial cell cultures. Functional studies include the assessment of the blood-retinal barrier (BRB), cell adhesion, and in vitro angiogenesis. In epiretinal membranes, endothelial cells and monocytes/macrophages express ADAMTS13. The levels of VWF, the platelet marker CD41, ADAMTS13, and the biomarkers of endothelial cell injury soluble VE-cadherin and soluble syndecan-1 are increased in PDR vitreous. ADAMTS13 is downregulated in diabetic rat retinas. The intravitreal administration of ADAMTS13 attenuates diabetes-induced BRB breakdown, the downregulation of VE-cadherin and β-catenin, and the upregulation of VWF, CD41, phospho-ERK1/2, HMGB1, VCAM-1, and ICAM-1. In Müller cells, ADAMTS13 attenuates MCP-1, MMP-9, and ROS upregulation induced by diabetic mimetic conditions. In HRMECs, ADAMTS13 attenuates the shedding of the soluble VE-cadherin and soluble syndecan-1 and the levels of phospho-ERK1/2, MCP-1, fractalkine, and ROS induced by diabetic mimetic conditions, the upregulation of ICAM-1 and VCAM-1 elicited by TNF-α, the adherence of monocytes induced by TNF-α, and VEGF-induced migration of human retinal microvascular endothelial cells. Our findings suggest that enhancing ADAMTS13 levels in situ ameliorates diabetes-induced retinal inflammation and vascular dysfunction.

MeSH

Diabetes Mellitus, Cells, Tissue Adhesions, Up-Regulation, Monocytes, Retina, Syndecan-1, Cadherins, Syndecans, Endothelial Cells, Blood Platelets, Retinaldehyde, Membranes, Diabetic Retinopathy, Epiretinal Membrane

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