Skip to main content Accessibility help

Lead promotes abnormal angiogenesis induced by CCM3 gene defects via mitochondrial pathway

  • Y. Sun (a1), H. Zhang (a2), X. Xing (a1), Z. Zhao (a1), J. He (a3), J. Li (a4), J. Chen (a1), M. Wang (a2) and Y. He (a1)...


Lead is one of the environmental pollutants with cardiovascular toxicity. The embryos are particularly sensitive to lead exposure, because it can move through the blood-placental barrier and the blood-brain barrier easily during embryonic development. Cerebral cavernous malformations 3 (CCM3) gene plays an important role in cardiovascular development, mainly affecting cell proliferation, differentiation and apoptosis. In this study, we established a blood vessel development model of mouse embryos in order to imitate human people with CCM3 genes defects and exposing to environment toxin Pb in utero. We would like to determine the interaction of Pb and CCM3 gene on vascular development, and to explore the mechanisms. We found that the yolk sac of CCM3 heterozygous mice embryo showed abnormal morphology at E11.5 after lead treatment comparing with wild type (WT) mice without lead exposure, meanwhile it showed more angiogenesis and vascular remodeling in the hematoxylin and eosin stained sections of the CCM3+/− yolk sac with lead exposure. We also found that the similar effect of Pb and CCM3 gene on mitochondrial DNA (mtDNA) copy number in vivo and in vitro. Mitochondrial morphology and function also changed in primary human umbilical vein endothelial cells after lead exposure. Besides, it was found that the HIF-1α and TFAM which have close relationship with mtDNA biogenesis showed similarly increasing messenger RNA expression in both human and mouse-derived primary cells with lead treated and CCM3 gene knockout. All of the above results indicated that lead and CCM3 might damage endothelial cells through mitochondria pathway and eventually both affected angiogenesis.


Corresponding author

*Address for correspondence: Prof. Y. He, Guangzhou Key Laboratory of Environmental Pollution and Risk Assessment, Sun Yat-sen University School of Public Health, Guangzhou, Guangdong 510080, China. (Email


Hide All
1. Needleman, H. Low level lead exposure: history and discovery. Ann Epidemiol. 2009; 19, 235238.
2. Gundacker, C, Hengstschläger, M. The role of the placenta in fetal exposure to heavy metals. Wien Med Wochenschr. 2012; 162, 201206.
3. Zhang, B, Xia, W, Li, Y, et al. Prenatal exposure to lead in relation to risk of preterm low birth weight: a matched case-control study in China. Reprod Toxicol. 2015; 57, 190195.
4. Su, X, Xing, X, Lai, G, et al. Effect of CCM3 gene defect on lead-induced cell genotoxicity in mouse embryonic fibroblasts. Chi J Prev Med. 2015; 49, 269274.
5. Hwang, J, Pallas, DC. STRIPAK complexes: structure, biological function, and involvement in human diseases. Int J Biochem Cell Biol. 2014; 47, 118148.
6. He, Y, Zhang, H, Yu, L, et al. Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal. 2010; 3, ra26.
7. Kelishadi, R, Poursafa, P. A review on the genetic, environmental, and lifestyle aspects of the early-life origins of cardiovascular disease. Curr Probl Pediatr Adolesc Health Care. 2014; 44, 5472.
8. Skogen, JC, Overland, S. The fetal origins of adult disease: a narrative review of the epidemiological literature. JRSM Short Rep. 2012; 3, 59.
9. Barker, DJ. Fetal nutrition and cardiovascular disease in later life. Br Med Bull. 1997; 53, 96108.
10. Tang, X, Luo, YX, Chen, HZ, Liu, DP. Mitochondria, endothelial cell function, and vascular diseases. Front Physiol. 2014; 5, 175.
11. Kluge, MA, Fetterman, JL, Vita, JA. Mitochondria and endothelial function. Circ Res. 2013; 112, 11711188.
12. Di Lisa, F, Kaludercic, N, Carpi, A, Menabò, R, Giorgio, M. Mitochondria and vascular pathology. Pharmacol Rep. 2009; 61, 123130.
13. Yang, SJ, Uriu-Adams, JY, Keen, CL, Rucker, RB, Lanoue, L. Effects of copper deficiency on mouse yolk sac vasculature and expression of angiogenic mediators. Birth Defects Res B Dev Reprod Toxicol. 2006; 77, 445454.
14. Nagy, A, Gertsenstein, M, Behringer, R. Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edn, 2002. Cold Spring Harbor Laboratory Press: New York.
15. Brown, NA, Fabro, S. Quantitation of rat embryonic development in vitro: a morphological scoring system. Teratology. 1981; 24, 6578.
16. Tasaki, T, Kim, ST, Zakrzewska, A, et al. UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role inyolk sac vascular development and autophagy. Proc Natl Acad Sci USA. 2013; 110, 38003805.
17. Rooney, JP, Ryde, IT, Sanders, LH, et al. CR based determination of mitochondrial DNA copy number in multipespecies. Methods Mol Biol. 2015; 1241, 2338.
18. Crampton, SP, Davis, J, Hughes, CC. Isolation of human umbilical vein endothelial cells (HUVEC). J Vis Exp. 2007; 3, 183.
19. Liu, J, Zhang, JF, Lu, JZ, et al. Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4. Acta Pharmacol Sin. 2013; 34, 137144.
20. Simons, TJ. Lead-calcium interactions in cellular lead toxicity. Neurotoxicology. 1993; 14, 7785.
21. Zhang, H, Ma, X, Peng, S, Nan, X, Zhao, H. Differential expression of MST4, STK25 and PDCD10 between benign prostatic hyperplasia and prostate cancer. Int J Clin Exp Pathol. 2014; 7, 81058111.
22. Hsu, CC, Wang, CH, Wu, LC, et al. Mitochondrial dysfunction represses HIF-1α protein synthesis through AMPK activation in human hepatoma HepG2 cells. Biochim Biophys Acta. 2013; 1830, 47434751.
23. Zhang, H, Gao, P, Fukuda, R, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respirat ion in VHL-deficient renal cell carcinoma byrepression of C-MYC activity. Cancer Cell. 2007; 11, 407420.
24. LaGory, EL, Wu, C, Taniguchi, CM, et al. Suppression of PGC-1α is critical for reprogramming oxidative metabolism in renal cell carcinoma. Cell Rep. 2015; 12, 116127.
25. De Bock, K, Georgiadou, M, Carmeliet, P. Role of endothelial cell metabolism in vessel sprouting. Cell Metab. 2013; 18, 634647.
26. Arany, Z, Foo, SY, Ma, Y, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008; 451, 10081012.
27. Płoszaj, T, Robaszkiewicz, A, Witas, H. Oxidative damage of mitochondrial DNA: the result or consequence of enhanced generation of reactive oxygen species. Postepy Biochem. 2010; 56, 139146.
28. Ercal, N, Gurer-Orhan, H, Aykin-Burns, N. Toxic metals and oxidative stress mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem. 2001; 1, 529539.
29. Youle, RJ, van der Bliek, AM. Mitochondrial fission, fusion, and stress. Science. 2012; 337, 10621065.
30. Rambold, AS, Lippincott-Schwartz, J. Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle. 2011; 10, 40324038.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed