BMP4 inhibits corneal neovascularization by interfering with tip cells in angiogenesis

• Published in: Experimental eye research 2023-12, Vol.237, p.109680-109680, Article 109680
• Main Authors: Nan, Weijin, He, Yuxi, Shen, Sitong, Wu, Meiliang, Wang, Shurong, Zhang, Yan
• Format: Article
• Language: English
• Subjects: Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - metabolism; Cornea - metabolism; Corneal Injuries - metabolism; Corneal neovascularization; Corneal Neovascularization - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Inflammation; Neovascularization, Physiologic; Neutrophil extracellular traps; Stalk cells; Tip cells; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2023.109680

Corneal neovascularization (CNV) can lead to impaired corneal transparency, resulting in vision loss or blindness. The primary pathological mechanism underlying CNV is an imbalance between pro-angiogenic and anti-angiogenic factors, with inflammation playing a crucial role. Notably, a vascular endothelial growth factor（VEGF）-A gradient triggers the selection of single endothelial cells（ECs） into primary tip cells that guide sprouting, while a dynamic balance between tip and stalk cells maintains a specific ratio to promote CNV. Despite the central importance of tip-stalk cell selection and shuffling, the underlying mechanisms remain poorly understood. In this study, we examined the effects of bone morphogenetic protein 4 (BMP4) on VEGF-A-induced lumen formation in human umbilical vein endothelial cells (HUVECs) and CD34-stained tip cell formation. In vivo, BMP4 inhibited CNV caused by corneal sutures. This process was achieved by BMP4 decreasing the protein expression of VEGF-A and VEGFR2 in corneal tissue after corneal suture injury. By observing the ultrastructure of the cornea, BMP4 inhibited the sprouting of tip cells and brought forward the appearance of intussusception. Meanwhile, BMP4 attenuated the inflammatory response by inhibiting neutrophil extracellular traps （NETs）formation through the NADPH oxidase-2（NOX-2）pathway. Our results indicate that BMP4 inhibits the formation of tip cells by reducing the generation of NETs, disrupting the dynamic balance of tip and stalk cells and thereby inhibiting CNV, suggesting that BMP4 may be a potential therapeutic target for CNV. [Display omitted] •The high prevalence of corneal neovascularization（CNV） is a serious blinding pathological change.•Neutrophil extracellular traps (NETs) induce a disorganized expansion of the inflammatory response and participate in CNV.•We found that BMP4 inhibits angiogenesis by suppressing tip cell and influencing the mechanism of tip cell formation.•We also innovatively found that NETs formation was present in the suture-induced CNV model and increased with time.•This work may provide a theoretical basis for BMP4 treatment of CNV.