title: Silica nanoparticles enhance autophagic activity, disturb endothelial cell homeostasis and impair angiogenesis.
abstract: BACKGROUND
  Given that the effects of ultrafine fractions (<0.1 μm) on ischemic heart diseases (IHD) and other cardiovascular diseases are gaining attention, this study is aimed to explore the influence of silica nanoparticles (SiNPs)-induced autophagy on endothelial cell homeostasis and angiogenesis.
  
  
  RESULTS
  Ultrastructural changes of autophagy were observed in both vascular endothelial cells and pericytes in the heart of ICR mice by TEM. Autophagic activity and impaired angiogenesis were further confirmed by the immunohistochemistry staining of LC3 and VEGFR2. In addition, the immunohistochemistry results showed that SiNPs had an inhibitory effect on ICAM-1 and VCAM-1, but no obvious effect on E-selectin in vivo. The disruption of F-actin cytoskeleton occurred as an initial event in SiNPs-treated endothelial cells. The depolarized mitochondria, autophagic vacuole accumulation, LC3-I/LC3-II conversion, and the down-regulation of cellular adhesion molecule expression were all involved in the disruption of endothelial cell homeostasis in vitro. Western blot analysis indicated that the VEGFR2/PI3K/Akt/mTOR and VEGFR2/MAPK/Erk1/2/mTOR signaling pathway was involved in the cardiovascular toxicity triggered by SiNPs. Moreover, there was a crosstalk between the VEGFR2-mediated autophagy signaling and angiogenesis signaling pathways.
  
  
  CONCLUSIONS
  In summary, the results demonstrate that SiNPs induce autophagic activity in endothelial cells and pericytes, subsequently disturb the endothelial cell homeostasis and impair angiogenesis. The VEGFR2-mediated autophagy pathway may play a critical role in maintaining endothelium and vascular homeostasis. Our findings may provide experimental evidence and explanation for cardiovascular diseases triggered by nano-sized particles.
authors.forename: Junchao
authors.initials: J
authors.lastname: Duan
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Peili
authors.initials: P
authors.lastname: Huang
authors.forename: Xianqing
authors.initials: X
authors.lastname: Zhou
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
authors.affiliation: School of Public Health, Capital Medical University, Beijing 100069, P,R, China. zwsun@hotmail.com.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006706:Homeostasis; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D053758:Nanoparticles / Q000633:toxicity*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010316:Particle Size; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D012822:Silicon Dioxide