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

Published online by Cambridge University Press:  07 November 2017

Y. Sun ,
H. Zhang ,
X. Xing ,
Z. Zhao ,
J. He ,
J. Li ,
J. Chen ,
M. Wang  and
Y. He
Y. Sun
Affiliation:
Guangzhou Key Laboratory of Environmental Pollution and Risk Assessment, Sun Yat-sen University School of Public Health, Guangzhou, Guangdong, China
H. Zhang
Affiliation:
Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT, USA
X. Xing
Affiliation:
Guangzhou Key Laboratory of Environmental Pollution and Risk Assessment, Sun Yat-sen University School of Public Health, Guangzhou, Guangdong, China
Z. Zhao
Affiliation:
Guangzhou Key Laboratory of Environmental Pollution and Risk Assessment, Sun Yat-sen University School of Public Health, Guangzhou, Guangdong, China
J. He
Affiliation:
MRC-Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK
J. Li
Affiliation:
Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
J. Chen
Affiliation:
Guangzhou Key Laboratory of Environmental Pollution and Risk Assessment, Sun Yat-sen University School of Public Health, Guangzhou, Guangdong, China
M. Wang
Affiliation:
Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT, USA
Y. He*
Affiliation:
Guangzhou Key Laboratory of Environmental Pollution and Risk Assessment, Sun Yat-sen University School of Public Health, Guangzhou, Guangdong, China
*
*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 heyun7@mail.sysu.edu.cn)
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Abstract

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.

Keywords

angiogenesisCCM3gene–environment interactionmitochondrialPb
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 9 , Issue 2 , April 2018 , pp. 182 - 190
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2017 

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References

1. Needleman, H. Low level lead exposure: history and discovery. Ann Epidemiol. 2009; 19, 235–238.CrossRefGoogle ScholarPubMed
2. Gundacker, C, Hengstschläger, M. The role of the placenta in fetal exposure to heavy metals. Wien Med Wochenschr. 2012; 162, 201–206.Google Scholar
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, 190–195.CrossRefGoogle ScholarPubMed
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, 269–274.Google ScholarPubMed
5. Hwang, J, Pallas, DC. STRIPAK complexes: structure, biological function, and involvement in human diseases. Int J Biochem Cell Biol. 2014; 47, 118–148.CrossRefGoogle ScholarPubMed
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.Google Scholar
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, 54–72.Google Scholar
8. Skogen, JC, Overland, S. The fetal origins of adult disease: a narrative review of the epidemiological literature. JRSM Short Rep. 2012; 3, 59.Google Scholar
9. Barker, DJ. Fetal nutrition and cardiovascular disease in later life. Br Med Bull. 1997; 53, 96–108.CrossRefGoogle ScholarPubMed
10. Tang, X, Luo, YX, Chen, HZ, Liu, DP. Mitochondria, endothelial cell function, and vascular diseases. Front Physiol. 2014; 5, 175.CrossRefGoogle ScholarPubMed
11. Kluge, MA, Fetterman, JL, Vita, JA. Mitochondria and endothelial function. Circ Res. 2013; 112, 1171–1188.Google Scholar
12. Di Lisa, F, Kaludercic, N, Carpi, A, Menabò, R, Giorgio, M. Mitochondria and vascular pathology. Pharmacol Rep. 2009; 61, 123–130.Google Scholar
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, 445–454.CrossRefGoogle ScholarPubMed
14. Nagy, A, Gertsenstein, M, Behringer, R. Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edn, 2002. Cold Spring Harbor Laboratory Press: New York.Google Scholar
15. Brown, NA, Fabro, S. Quantitation of rat embryonic development in vitro: a morphological scoring system. Teratology. 1981; 24, 65–78.Google Scholar
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, 3800–3805.CrossRefGoogle Scholar
17. Rooney, JP, Ryde, IT, Sanders, LH, et al. CR based determination of mitochondrial DNA copy number in multipespecies. Methods Mol Biol. 2015; 1241, 23–38.Google Scholar
18. Crampton, SP, Davis, J, Hughes, CC. Isolation of human umbilical vein endothelial cells (HUVEC). J Vis Exp. 2007; 3, 183.Google Scholar
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, 137–144.Google Scholar
20. Simons, TJ. Lead-calcium interactions in cellular lead toxicity. Neurotoxicology. 1993; 14, 77–85.Google Scholar
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, 8105–8111.Google ScholarPubMed
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, 4743–4751.Google Scholar
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, 407–420.CrossRefGoogle Scholar
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, 116–127.Google Scholar
25. De Bock, K, Georgiadou, M, Carmeliet, P. Role of endothelial cell metabolism in vessel sprouting. Cell Metab. 2013; 18, 634–647.CrossRefGoogle ScholarPubMed
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, 1008–1012.CrossRefGoogle ScholarPubMed
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, 139–146.Google Scholar
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, 529–539.Google Scholar
29. Youle, RJ, van der Bliek, AM. Mitochondrial fission, fusion, and stress. Science. 2012; 337, 1062–1065.CrossRefGoogle ScholarPubMed
30. Rambold, AS, Lippincott-Schwartz, J. Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle. 2011; 10, 4032–4038.Google Scholar