The CXCR4/miR-1910-5p/MMRN2 Axis Is Involved in Corneal Neovascularization by Affecting Vascular Permeability

Abstract

Purpose Chemokine receptor 4 (CXCR4) plays an essential role in the early stage of corneal neovascularization (CNV), but the underlying key molecular mechanism has yet to be addressed. This study aimed to explore the new molecular mechanism of CXCR4 in CNV and the related pathological events. Methods CXCR4 was assayed by immunofluorescence or Western blotting. The function of the supernatant from hypoxia-treated human corneal epithelial cells (HCE-T) cells was examined by culturing with human umbilical vein endothelial cells. MicroRNA sequencing was used to detect the downstream microRNAs upon CXCR4 knockdown and analyzed by preliminary bioinformatics. The proangiogenic functions and downstream target genes of microRNA were investigated by gene interference and luciferase assay. An alkali-burned murine model was introduced to examine the function and mechanism of miR-1910-5p in vivo. Results High CXCR4 expression was confirmed in corneal tissues of patients with CNV and hypoxic HCE-T cells. The supernatant from hypoxia-treated HCE-T cells is involved in the CXCR4-mediated angiogenesis of human umbilical vein endothelial cells. Notably, miR-1910-5p was demonstrated to be at a high level in wild-type HCE-T cells and its supernatant, and in CNV patient tears. The proangiogenic functions of miR-1910-5p were demonstrated with the assays of cell migration, tube formation, and aortic ring. Moreover, miR-1910-5p significantly inhibited multimerin-2 expression by targeting its 3ʹ untranslated region and caused significant extracellular junctional defects in human umbilical vein endothelial cells. MiR-1910-5p antagomir could significantly increase multimerin-2 level and decrease vascular leakage, and ultimately inhibit CNV in a murine model. Conclusions Our results revealed a novel CXCR4-mediated mechanism and proved that targeting the miR-1910-5p/multimerin-2 pathway could be a promising therapeutic target for CNV.

Inhibition of Cxcr4 Disrupts Mouse Embryonic Palatal Mesenchymal Cell Migration and Induces Cleft Palate Occurrence

“…C-X-C motif chemokine receptor 4 (CXCR4) is a G protein-coupled receptor that participates in cell homing and chemotaxis in hematopoietic and immune systems [ 19 ]. CXCR4 is widely expressed in human tissues, such as corneal [ 20 ], lung [ 21 ],bone marrow [ 22 ], etc. It is involved in a variety of biological processes, including angiogenesis, embryonic development, and the regulation of hematopoietic stem cell homing [ 23 ], while mice with homozygous knockout of Cxcr4 will die before birth [ 24 ].…”