Current Environmental Health Reports

, Volume 3, Issue 4, pp 379–391 | Cite as

Metal Nanomaterial Toxicity Variations Within the Vascular System

  • Alaeddin B. Abukabda
  • Phoebe A. Stapleton
  • Timothy R. NurkiewiczEmail author
Metals and Health (A Barchowsky, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Metals and Health


Engineered nanomaterials (ENM) are anthropogenic materials with at least one dimension less than 100 nm. Their ubiquitous employment in biomedical and industrial applications in the absence of full toxicological assessments raises significant concerns over their safety on human health. This is a significant concern, especially for metal and metal oxide ENM as they may possess the greatest potential to impair human health. A large body of literature has developed that reflects adverse systemic effects associated with exposure to these materials, but an integrated mechanistic framework for how ENM exposure influences morbidity remains elusive. This may be due in large part to the tremendous diversity of existing ENM and the rate at which novel ENM are produced. In this review, the influence of specific ENM physicochemical characteristics and hemodynamic factors on cardiovascular toxicity is discussed. Additionally, the toxicity of metallic and metal oxide ENM is presented in the context of the cardiovascular system and its discrete anatomical and functional components. Finally, future directions and understudied topics are presented. While it is clear that the nanotechnology boom has increased our interest in ENM toxicity, it is also evident that the field of cardiovascular nanotoxicology remains in its infancy and continued, expansive research is necessary in order to determine the mechanisms via which ENM exposure contributes to cardiovascular morbidity.


Engineered nanomaterials Metal Metal oxides Cardiovascular system Microcirculation 



The authors would like to thank Caroll McBride for his expert technical support during the completion of this review and Elizabeth Dalton for her assistance in the development of Fig. 1. This work was supported by the following sources: National Institutes of Health R01-ES015022 (TRN) and K99-ES024783 (PAS) and the National Science Foundation Cooperative Agreement-DGE-1144676 (TRN, ABA).

Compliance With Ethical Standards

Conflict of Interest

Alaeddin B. Abukabda, Phoebe A. Stapleton, and Timothy R. Nurkiewicz declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    National Nanotechnology Coordination Office. National Science and Technology Council Committee on Technology Subcommittee on Nanoscale Science Engineering and Technology; National Science and Technology Council, editor. The National Nanotechnology Initiative, Supplement to the President’s FY2012 Budget. 1–50. 2012. Ref Type: ReportGoogle Scholar
  2. 2.
    Newby DE, Mannucci PM, Tell GS, et al. Expert position paper on air pollution and cardiovascular disease. Eur Heart J. 2015;36(2):83–93b.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhu M, Nie G, Meng H, et al. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate. Acc Chem Res. 2013;46(3):622.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Kirchner C, Liedl T, Kudera S, et al. Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. Nano Lett. 2005;5(2):331–8.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Bystrzejewska-Piotrowska G, Golimowski J, Urban PL. Nanoparticles: their potential toxicity, waste and environmental management. Waste Manag. 2009;29(9):2587–95.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Tsuda A, Butler JP, Fredberg JJ. Effects of alveolated duct structure on aerosol kinetics. I. Diffusional deposition in the absence of gravity. J Appl Physiol (1985). 1994;76(6):2497–509.Google Scholar
  7. 7.
    Tsuda A, Henry FS, Butler JP. Particle transport and deposition: basic physics of particle kinetics. Compr Physiol. 2013;3(4):1437–71.PubMedPubMedCentralGoogle Scholar
  8. 8••.
    Stapleton PA, Nurkiewicz TR. Vascular distribution of nanomaterials. Wiley. Interdiscip. Rev. Nanomed Nanobiotechnol. 2014;6(4):338–48 This work describes ENM distribution within the vasculature and the adverse effects in each distinct vascular segment.Google Scholar
  9. 9.
    Pries AR, Secomb TW. Rheology of the microcirculation. Clin Hemorheol Microcirc. 2003;29(3–4):143–8.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Popel AS, Johnson PC. Microcirculation and hemorheology. Annu Rev Fluid Mech. 2005:3743–69.Google Scholar
  11. 11.
    Kolanjiyil AV, Kleinstreuer C. Nanoparticle mass transfer from lung airways to systemic regions—part I: whole-lung aerosol dynamics. J Biomech Eng. 2013;135(12):121003.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Kreyling WG, Semmler-Behnke M, Moller W. Ultrafine particle-lung interactions: does size matter? J Aerosol Med. 2006;19(1):74–83.PubMedPubMedCentralGoogle Scholar
  13. 13••.
    Kreyling WG, Semmler-Behnke M, Seitz J, et al. Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs. Inhal Toxicol. 2009;(21 Suppl):155–60 This study establishes the ability of inhaled nanoparticles to translocate to extrapulmonary compartments and tissues.Google Scholar
  14. 14.
    Palombo M, Deshmukh M, Myers D, et al. Pharmaceutical and toxicological properties of engineered nanomaterials for drug delivery. Annu. Rev. Pharmacol. Toxicol. 2014:54581–98.Google Scholar
  15. 15.
    Liu HH, Surawanvijit S, Rallo R, et al. Analysis of nanoparticle agglomeration in aqueous suspensions via constant-number Monte Carlo simulation. Environ Sci Technol. 2011;45(21):9284–92.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Sadauskas E, Jacobsen NR, Danscher G, et al. Biodistribution of gold nanoparticles in mouse lung following intratracheal instillation. Chem. Cent. J. 2009; 316.Google Scholar
  17. 17.
    Bertrand N, Leroux JC. The journey of a drug-carrier in the body: an anatomo-physiological perspective. J Control Release. 2012;161(2):152–63.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Takenaka S, Karg E, Kreyling WG, et al. Distribution pattern of inhaled ultrafine gold particles in the rat lung. Inhal Toxicol. 2006;18(10):733–40.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Singh S, Shi T, Duffin R, et al. Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles. Toxicol Appl Pharmacol. 2007;222:141–51.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Rejman J, Oberle V, Zuhorn IS, et al. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(Pt 1):159–69.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Conner SD, Schmid SL. Differential requirements for AP-2 in clathrin-mediated endocytosis. J Cell Biol. 2003;162(5):773–9.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Arredouani MS, Franco F, Imrich A, et al. Scavenger receptors SR-AI/II and MARCO limit pulmonary dendritic cell migration and allergic airway inflammation. J Immunol. 2007;178(9):5912–20.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Kanno Y, Miyama Y, Takane Y, et al. Identification of intracellular localization signals and of mechanisms underlining the nucleocytoplasmic shuttling of human aryl hydrocarbon receptor repressor. Biochem Biophys Res Commun. 2007;364(4):1026–31.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Muhlfeld C, Gehr P, Rothen-Rutishauser B. Translocation and cellular entering mechanisms of nanoparticles in the respiratory tract. Swiss Med Wkly. 2008;138(27–28):387–91.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Kreyling WG, Hirn S, Moller W, et al. Air-blood barrier translocation of tracheally instilled gold nanoparticles inversely depends on particle size. ACS Nano. 2014;8(1):222–33.PubMedPubMedCentralGoogle Scholar
  26. 26.
    De Jong WH, Hagens WI, Krystek P, et al. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials. 2008;29(12):1912–9.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Deshmukh M, Kutscher HL, Gao D, et al. Biodistribution and renal clearance of biocompatible lung targeted poly (ethylene glycol) (PEG) nanogel aggregates. J Control Release. 2012;164(1):65–73.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Brenner BM, Hostetter TH, Humes HD. Glomerular permselectivity: barrier function based on discrimination of molecular size and charge. Am J Phys. 1978;234(6):F455–60.Google Scholar
  29. 29.
    Brenner BM, Hostetter TH, Humes HD. Molecular basis of proteinuria of glomerular origin. N Engl J Med. 1978;298(15):826–33.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Yoffe AD. Low-dimensional systems-quantum-size effects and electronic-properties of semiconductor microcrystallites (zero-dimensional systems) and some quasi-2-dimensional systems. Adv Phys. 1993;42(2):173–266.Google Scholar
  31. 31.
    Shubayev VI, Pisanic TR, Jin S. Magnetic nanoparticles for theragnostics. Adv Drug Deliv Rev. 2009;61(6):467–77.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Chithrani DB. Intracellular uptake, transport, and processing of gold nanostructures. Mol Membr Biol. 2010;27(7):299–311.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Lundqvist M, Stigler J, Elia G, et al. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci U S A. 2008;105(38):14265–70.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Chithrani DB, Dunne M, Stewart J, et al. Cellular uptake and transport of gold nanoparticles incorporated in a liposomal carrier. Nanomedicine. 2010;6(1):161–9.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Xia T, Kovochich M, Liong M, et al. Polyethyleneimine coating enhances the cellular uptake of mesoporous silica nanoparticles and allows safe delivery of siRNA and DNA constructs. ACS Nano. 2009;3(10):3273–86.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Hirn S, Semmler-Behnke M, Schleh C, et al. Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur J Pharm Biopharm. 2011;77(3):407–16.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Nemmar A, Hoet PH, Vanquickenborne B, et al. Passage of inhaled particles into the blood circulation in humans. Circulation. 2002;105(4):411–4.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Chonn A, Cullis PR, Devine DV. The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J Immunol. 1991;146(12):4234–41.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Li R, Wang X, Ji Z, et al. Surface charge and cellular processing of covalently functionalized multiwall carbon nanotubes determine pulmonary toxicity. ACS Nano. 2013;7(3):2352–68.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Rajagopalan S, Brook RD. The indoor-outdoor air-pollution continuum and the burden of cardiovascular disease: an opportunity for improving global health. Glob Heart. 2012;7(3):207–13.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Illum SL, Davis SS. Effect of the nonionic surfactant poloxamer 338 on the fate and deposition of polystyrene microspheres following intravenous administration. J Pharm Sci. 1983;72(9):1086–9.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Allen TM, Chonn A. Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett. 1987;223(1):42–6.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Moore A, Marecos E, Bogdanov Jr A, et al. Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model. Radiology. 2000;214(2):568–74.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Klibanov AL, Maruyama K, Beckerleg AM, et al. Activity of amphipathic poly (ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim Biophys Acta. 1991;1062(2):142–8.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Honary S, Ebrahimi P, Hadianamrei R. Optimization of size and encapsulation efficiency of 5-FU loaded chitosan nanoparticles by response surface methodology. Curr Drug Deliv. 2013;10(6):742–52.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Zhang H, Cui H. Synthesis and characterization of functionalized ionic liquid-stabilized metal (gold and platinum) nanoparticles and metal nanoparticle/carbon nanotube hybrids. Langmuir. 2009;25(5):2604–12.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Dougherty GM, Rose KA, Tok JB, et al. The zeta potential of surface-functionalized metallic nanorod particles in aqueous solution. Electrophoresis. 2008;29(5):1131–9.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Rittermeier A, Miao S, MK S, et al. The formation of colloidal copper nanoparticles stabilized by zinc stearate: one-pot single-step synthesis and characterization of the core-shell particles. Phys Chem ChemPhys. 2009;11(37):8358–66.Google Scholar
  49. 49.
    Alkilany AM, Thompson LB, Boulos SP, et al. Gold nanorods: their potential for photothermal therapeutics and drug delivery, tempered by the complexity of their biological interactions. Adv Drug Deliv Rev. 2012;64(2):190–9.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Podila R, Chen R, Ke PC, et al. Effects of surface functional groups on the formation of nanoparticle-protein corona. Appl Phys Lett. 2012;101(26):263701.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Shannahan JH, Podila R, Aldossari AA, et al. Formation of a protein corona on silver nanoparticles mediates cellular toxicity via scavenger receptors. Toxicol Sci. 2015;143(1):136–46.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Dobrovolskaia MA, Patri AK, Zheng J, et al. Interaction of colloidal gold nanoparticles with human blood: effects on particle size and analysis of plasma protein binding profiles. Nanomedicine. 2009;5(2):106–17.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Walkey CD, Olsen JB, Guo H, et al. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc. 2012;134(4):2139–47.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Champion JA, Walker A, Mitragotri S. Role of particle size in phagocytosis of polymeric microspheres. Pharm Res. 2008;25(8):1815–21.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Sato Y, Yokoyama A, Shibata K, et al. Influence of length on cytotoxicity of multi-walled carbon nanotubes against human acute monocytic leukemia cell line THP-1 in vitro and subcutaneous tissue of rats in vivo. Mol BioSyst. 2005;1(2):176–82.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Sharma J, Tai Y, Imae T. Biomodulation approach for gold nanoparticles: synthesis of anisotropic to luminescent particles. Chem Asian J. 2010;5(1):70–3.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang Y, Guo S, Chen H, et al. Facile fabrication of large area of aggregated gold nanorods film for efficient surface-enhanced Raman scattering. J Colloid Interface Sci. 2008;318(1):82–7.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Wang J, Byrne JD, Napier ME, et al. More effective nanomedicines through particle design. Small. 2011;7(14):1919–31.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Mody VV, Siwale R, Singh A, et al. Introduction to metallic nanoparticles. J Pharm Bioallied Sci. 2010;2(4):282–9.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Freese C, Uboldi C, Gibson MI, et al. Uptake and cytotoxicity of citrate-coated gold nanospheres: comparative studies on human endothelial and epithelial cells. Part Fibre. Toxicol. 2012; 923.Google Scholar
  61. 61.
    Pan Y, Wu Q, Qin L, et al. Gold nanoparticles inhibit VEGF165-induced migration and tube formation of endothelial cells via the Akt pathway. Biomed ResInt. 2014:2014418624.Google Scholar
  62. 62.
    Dulak J, Jozkowicz A. Regulation of vascular endothelial growth factor synthesis by nitric oxide: facts and controversies. Antioxid Redox Signal. 2003;5(1):123–32.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Trickler WJ. Lantz-McPeak SM, Robinson BL, et al. Porcine brain microvessel endothelial cells show pro-inflammatory response to the size and composition of metallic nanoparticles. Drug Metab Rev. 2014;46(2):224–31.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Abdelhalim MA, Jarrar BM. Gold nanoparticles administration induced prominent inflammatory, central vein intima disruption, fatty change and Kupffer cells hyperplasia. Lipids Health Dis. 2011; 10133.Google Scholar
  65. 65.
    Alkilany AM, Shatanawi A, Kurtz T, et al. Toxicity and cellular uptake of gold nanorods in vascular endothelium and smooth muscles of isolated rat blood vessel: importance of surface modification. Small. 2012;8(8):1270–8.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Soloviev A, Zholos A, Ivanova I, et al. Plasmonic gold nanoparticles possess the ability to open potassium channels in rat thoracic aorta smooth muscles in a remote control manner. Vasc Pharmacol. 2015:72190–6.Google Scholar
  67. 67.
    Bosetti M, Masse A, Tobin E, et al. Silver coated materials for external fixation devices: in vitro biocompatibility and genotoxicity. Biomaterials. 2002;23(3):887–92.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Dibrov P, Dzioba J, Gosink KK, et al. Chemiosmotic mechanism of antimicrobial activity of Ag(+) in Vibrio cholerae. Antimicrob Agents Chemother. 2002;46(8):2668–70.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Li WR, Xie XB, Shi QS, et al. Antibacterial effect of silver nanoparticles on Staphylococcus aureus. Biometals. 2011;24(1):135–41.PubMedPubMedCentralGoogle Scholar
  70. 70.
    DD Jr E, Chumanov G. Synthesis and optical properties of silver nanoparticles and arrays. ChemPhysChem. 2005;6(7):1221–31.Google Scholar
  71. 71.
    Berciaud S, Cognet L, Lounis B. Photothermal absorption spectroscopy of individual semiconductor nanocrystals. Nano Lett. 2005;5(11):2160–3.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Gurunathan S, Lee KJ, Kalishwaralal K, et al. Antiangiogenic properties of silver nanoparticles. Biomaterials. 2009;30(31):6341–50.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Trickler WJ, Lantz SM, Murdock RC, et al. Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells. Toxicol Sci. 2010;118(1):160–70.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Castiglioni S, Caspani C, Cazzaniga A, et al. Short- and long-term effects of silver nanoparticles on human microvascular endothelial cells. World J Biol Chem. 2014;5(4):457–64.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Gonzalez C, Rosas-Hernandez H, Ramirez-Lee MA, et al. Role of silver nanoparticles (AgNPs) on the cardiovascular system. Arch Toxicol. 2016;90(3):493–511.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Guo H, Zhang J, Boudreau M, et al. Intravenous administration of silver nanoparticles causes organ toxicity through intracellular ROS-related loss of inter-endothelial junction. Part Fibre. Toxicol. 2016; 1321.Google Scholar
  77. 77.
    Shi J, Sun X, Lin Y, et al. Endothelial cell injury and dysfunction induced by silver nanoparticles through oxidative stress via IKK/NF-kappa B pathways. Biomaterials. 2014;35(24):6657–66.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Chatterjee AK, Chakraborty R, Basu T. Mechanism of antibacterial activity of copper nanoparticles. Nanotechnology. 2014;25(13):135101.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Sun J, Wang S, Zhao D, et al. Cytotoxicity, permeability, and inflammation of metal oxide nanoparticles in human cardiac microvascular endothelial cells: cytotoxicity, permeability, and inflammation of metal oxide nanoparticles. Cell Biol Toxicol. 2011;27(5):333–42.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Mroczek-Sosnowska N, Lukasiewicz M, Wnuk A, et al. In ovo administration of copper nanoparticles and copper sulfate positively influences chicken performance. J. Sci. Food Agric. 2015.Google Scholar
  81. 81.
    Mroczek-Sosnowska N, Sawosz E, Vadalasetty KP, et al. Nanoparticles of copper stimulate angiogenesis at systemic and molecular level. Int J Mol Sci. 2015;16(3):4838–49.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Kalishwaralal K, Sheikpranbabu S. Barath Mani Kanth S, et al. Gold nanoparticles inhibit vascular endothelial growth factor-induced angiogenesis and vascular permeability via Src dependent pathway in retinal endothelial cells. Angiogenesis. 2011;14(1):29–45.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Gerber HP, Hillan KJ, Ryan AM, et al. VEGF is required for growth and survival in neonatal mice. Development. 1999;126(6):1149–59.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Kubo H, Alitalo K. The bloody fate of endothelial stem cells. Genes Dev. 2003;17(3):322–9.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Schatteman GC, Awad O. Hemangioblasts, angioblasts, and adult endothelial cell progenitors. Anat. Rec. A Discov. Mol. Cell Evol Biol. 2004;276(1):13–21.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Miquerol L, Langille BL, Nagy A. Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development. 2000;127(18):3941–6.PubMedPubMedCentralGoogle Scholar
  87. 87.
    NIOSH, DHHS. Current intelligence. Bulletin 63—occupational exposure to titanium dioxide. 2011.Google Scholar
  88. 88.
    Silva RM, Teesy C, Franzi L, et al. Biological response to nano-scale titanium dioxide (TiO2): role of particle dose, shape, and retention. J. Toxicol. Environ. Health A. 2013;76(16):953–72.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Nurkiewicz TR, Porter DW, Barger M, et al. Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure. Environ Health Perspect. 2006;114(3):412–9.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Hougaard KS, Jackson P, Jensen KA, et al. Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part Fibre. Toxicol. 2010; 716.Google Scholar
  91. 91.
    Warheit DB, Webb TR, Reed KL, et al. Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential responses related to surface properties. Toxicology. 2007;230(1):90–104.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Cui Y, Liu H, Ze Y, et al. Gene expression in liver injury caused by long-term exposure to titanium dioxide nanoparticles in mice. Toxicol Sci. 2012;128(1):171–85.PubMedPubMedCentralGoogle Scholar
  93. 93.
    LeBlanc AJ, Cumpston JL, Chen BT, et al. Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles. J Toxicol Environ Health A. 2009;72(24):1576–84.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Stapleton PA, McBride CR, Yi J, et al. Uterine microvascular sensitivity to nanomaterial inhalation: an in vivo assessment. Toxicol Appl Pharmacol. 2015;288(3):420–8.PubMedPubMedCentralGoogle Scholar
  95. 95••.
    Nurkiewicz, TR, Porter, DW, Hubbs, AF, et al. Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction. Part Fibre. Toxicol. 2008; 51. This study indicates that nanoparticle inhalation impairs microvascular function more significantly than exposure to micron-sized particles of similar elemental composition.Google Scholar
  96. 96.
    Nurkiewicz TR, Porter DW, Hubbs AF, et al. Pulmonary nanoparticle exposure disrupts systemic microvascular nitric oxide signaling. Toxicol Sci. 2009;110(1):191–203.PubMedPubMedCentralGoogle Scholar
  97. 97.
    LeBlanc AJ, Moseley AM, Chen BT, et al. Nanoparticle inhalation impairs coronary microvascular reactivity via a local reactive oxygen species-dependent mechanism. Cardiovasc Toxicol. 2010;10(1):27–36.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Knuckles TL, Yi J, Frazer DG, et al. Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways. Nanotoxicology. 2012;6(7):724–35.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Abboud FM. The sympathetic nervous system and alpha adrenergic blocking agents in shock. Med Clin North Am. 1968;52(5):1049–60.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Kan H, Wu Z, Lin YC, et al. The role of nodose ganglia in the regulation of cardiovascular function following pulmonary exposure to ultrafine titanium dioxide. Nanotoxicology. 2014;8(4):447–54.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000;102(4):470–9.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Cassee FR, van Balen EC, Singh C, et al. Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. Crit Rev Toxicol. 2011;41(3):213–29.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Colon J, Herrera L, Smith J, et al. Protection from radiation-induced pneumonitis using cerium oxide nanoparticles. Nanomedicine. 2009;5(2):225–31.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Yokel RA, Tseng MT, Dan M, et al. Biodistribution and biopersistence of ceria engineered nanomaterials: size dependence. Nanomedicine. 2013;9(3):398–407.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Yokel RA, TC A, MacPhail R, et al. Distribution, elimination, and biopersistence to 90 days of a systemically introduced 30 nm ceria-engineered nanomaterial in rats. Toxicol Sci. 2012;127(1):256–68.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Gojova A, Lee JT, Jung HS, et al. Effect of cerium oxide nanoparticles on inflammation in vascular endothelial cells. Inhal Toxicol. 2009;21:1123–30.Google Scholar
  107. 107.
    Minarchick VC, Stapleton PA, Porter DW, et al. Pulmonary cerium dioxide nanoparticle exposure differentially impairs coronary and mesenteric arteriolar reactivity. Cardiovasc Toxicol. 2013;13(4):323–37.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Minarchick VC, Stapleton PA, Sabolsky EM, et al. Cerium dioxide nanoparticle exposure improves microvascular dysfunction and reduces oxidative stress in spontaneously hypertensive rats. Front Physiol 2015; 6339.Google Scholar
  109. 109.
    Minarchick VC, Stapleton PA, Fix NR, et al. Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling. Toxicol Sci. 2015;144(1):77–89.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Gupta AK, Curtis AS. Lactoferrin and ceruloplasmin derivatized superparamagnetic iron oxide nanoparticles for targeting cell surface receptors. Biomaterials. 2004;25(15):3029–40.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Brittenham GM. New advances in iron metabolism, iron deficiency, and iron overload. Curr Opin Hematol. 1994;1(2):101–6.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Horwitz LD, Rosenthal EA. Iron-mediated cardiovascular injury. Vasc Med. 1999;4(2):93–9.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Buyukhatipoglu K, Clyne AM. Superparamagnetic iron oxide nanoparticles change endothelial cell morphology and mechanics via reactive oxygen species formation. J Biomed Mater Res A. 2011;96(1):186–95.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Buyukhatipoglu K, Miller TA, Clyne AM. Flame synthesis and in vitro biocompatibility assessment of superparamagnetic iron oxide nanoparticles: cellular uptake, toxicity and proliferation studies. J Nanosci Nanotechnol. 2009;9(12):6834–43.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Apopa PL, Qian Y, Shao R, et al. Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling. Part Fibre. Toxicol. 2009; 61.Google Scholar
  116. 116.
    Zhu MT, Wang Y, Feng WY, et al. Oxidative stress and apoptosis induced by iron oxide nanoparticles in cultured human umbilical endothelial cells. J Nanosci Nanotechnol. 2010;10(12):8584–90.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Wu X, Tan Y, Mao H, et al. Toxic effects of iron oxide nanoparticles on human umbilical vein endothelial cells. Int J Nanomedicine. 2010:5385–99.Google Scholar
  118. 118.
    Nemmar A, Beegam S, Yuvaraju P, et al. Ultrasmall superparamagnetic iron oxide nanoparticles acutely promote thrombosis and cardiac oxidative stress and DNA damage in mice. Part fibre. Toxicol. 2016;13(1):22.Google Scholar
  119. 119.
    Sharma V, Singh P, Pandey AK, et al. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res. 2012;745(1–2):84–91.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Kim YH, Fazlollahi F, Kennedy IM, et al. Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure. Am. J. Respir. Crit Care Med. 2010;182(11):1398–409.Google Scholar
  121. 121.
    Xia T, Kovochich M, Liong M, et al. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano. 2008;2(10):2121–34.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Gojova A, Guo B, Kota RS, et al. Induction of inflammation in vascular endothelial cells by metal oxide nanoparticles: effect of particle composition. Environ Health Perspect. 2007;115(3):403–9.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Paszek E, Czyz J, Woznicka O, et al. Zinc oxide nanoparticles impair the integrity of human umbilical vein endothelial cell monolayer in vitro. J Biomed Nanotechnol. 2012;8(6):957–67.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Tsou TC, Yeh SC, Tsai FY, et al. Zinc oxide particles induce inflammatory responses in vascular endothelial cells via NF-kappa B signaling. J Hazard Mater. 2010;183(1–3):182–8.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Moller W, Felten K, Sommerer K, et al. Deposition, retention, and translocation of ultrafine particles from the central airways and lung periphery. Am. J. Respir. Crit Care Med. 2008;177(4):426–32.Google Scholar
  126. 126.
    Oberdorster G, Maynard A, Donaldson K, et al. Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy. Part Fibre. Toxicol. 2005; 28.Google Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Alaeddin B. Abukabda
    • 1
    • 2
  • Phoebe A. Stapleton
    • 3
  • Timothy R. Nurkiewicz
    • 1
    • 2
    Email author
  1. 1.Center for Cardiovascular and Respiratory SciencesWest Virginia University School of MedicineMorgantownUSA
  2. 2.Department of Physiology and PharmacologyWest Virginia University School of MedicineMorgantownUSA
  3. 3.Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Environmental and Occupational Health Sciences InstituteRutgers UniversityPiscatawayUSA

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