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In this study, we aimed to explore the role of nitric oxide (NO) in regulating angiogenesis in cerebral cavernous malformations 3 gene (CCM3)-deficient mice exposed to lead during vascular development; further, we aimed to identify and study the potential mechanism involved as well. Angiogenesis was detected by whole mount immunofluorescent staining of retinal vessels in WT and CCM3+/- mice. Brain microvascular endothelial cells (BMECs) isolated from WT and CCM3+/- mice, primary HUVECs, and immortalized HUVECs (imHUVECs) (CCM3+/+ and CCM3-/-) were used and treated with lead acetate (PbAc). RT-PCR and Western blotting were used to detect the mRNA and protein expression of iNOS, eNOS, and VEGF genes. The results showed that both lead exposure and CCM3 gene deficiency adversely affected endothelial cell function, causing abnormal angiogenesis and vascular remodeling. The mRNA expression of eNOS and iNOS was significantly different in WT and CCM3+/- BMECs (0.04 ± 0.001 vs. 0.016 ± 0.002; 0.26 ± 0.002 vs. 0.306 ± 0.002, respectively), and the expression of eNOS and iNOS in imHUVECs (CCM3+/+ and CCM3-/-) also increased after PbAc exposure. In conclusion, CCM3 gene-deficient mice were more susceptible to abnormal vascular development after low-level lead exposure, probably due to the release of NO. Copyright © 2020 Elsevier B.V. All rights reserved.


Yi Sun, Zhiqiang Zhao, Haifeng Zhang, Jiong Li, Jingli Chen, Xiaoyi Luan, Wang Min, Yun He. The interaction of lead exposure and CCM3 defect plays an important role in regulating angiogenesis through eNOS/NO pathway. Environmental toxicology and pharmacology. 2020 Oct;79:103407

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PMID: 32512318

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