Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China; Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Exp Eye Res. 2022 Jul;220:109125. doi: 10.1016/j.exer.2022.109125. Epub 2022 May 23.
The normal cornea has no blood vessels but has abundant innervation. There is emerging evidence that sensory nerves, originated from the trigeminal ganglion (TG) neurons, play a key role in corneal angiogenesis. In the current study, we examined the role of TG sensory neuron-derived calcitonin gene-related peptide (CGRP) in promoting corneal neovascularization (CNV). We found that CGRP was expressed in the TG and cultured TG neurons. In the cornea, minimal CGRP mRNA was detected and CGRP immunohistochemical staining was exclusively co-localized with corneal nerves, suggesting corneal nerves are likely the source of CGRP in the cornea. In response to intrastromal suture placement and neovascularization in the cornea, CGRP expression was increased in the TG. In addition, we showed that CGRP was potently pro-angiogenic, leading to vascular endothelial cell (VEC) proliferation, migration, and tube formation in vitro and corneal hemangiogenesis and lymphangiogenesis in vivo. In a co-culture system of TG neurons and VEC, blocking CGRP signaling in the conditioned media of TG neurons led to decreased VEC migration and tube formation. More importantly, subconjunctival injection of a CGRP antagonist CGRP8-37 reduced suture-induced corneal hemangiogenesis and lymphangiogenesis in vivo. Taken together, our data suggest that TG sensory neuron and corneal nerve-derived CGRP promotes corneal angiogenesis.
正常角膜没有血管，但有丰富的神经支配。有新的证据表明，感觉神经（来源于三叉神经节神经元）在角膜血管生成中起着关键作用。在本研究中，我们研究了三叉神经节感觉神经元衍生的降钙素基因相关肽（CGRP）在促进角膜新生血管形成（CNV）中的作用。我们发现 CGRP 在三叉神经节和培养的三叉神经节神经元中表达。在角膜中，检测到最低水平的 CGRP mRNA，CGRP 免疫组织化学染色仅与角膜神经共定位，表明角膜神经可能是角膜中 CGRP 的来源。在角膜内基质缝线放置和新生血管形成的情况下，三叉神经节中的 CGRP 表达增加。此外，我们表明 CGRP 具有强大的促血管生成作用，导致体外血管内皮细胞（VEC）增殖、迁移和管形成，以及体内角膜血管生成和淋巴管生成。在三叉神经节神经元和 VEC 的共培养系统中，阻断三叉神经节神经元条件培养基中的 CGRP 信号导致 VEC 迁移和管形成减少。更重要的是，结膜下注射 CGRP 拮抗剂 CGRP8-37 可减少体内缝线诱导的角膜血管生成和淋巴管生成。综上所述，我们的数据表明三叉神经节感觉神经元和角膜神经衍生的 CGRP 促进角膜血管生成。
