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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 [email protected])
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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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