title: Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation.
abstract: Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) has been shown to disrupt endothelium-dependent arteriolar dilation in the peripheral microcirculation. The molecular mechanisms behind these arteriolar disruptions have yet to be fully elucidated. The secreted matricellular matrix protein thrombospondin-1 (TSP-1) is capable of moderating arteriolar vasodilation by inhibiting soluble guanylate cyclase activity. We hypothesized that TSP-1 may be a link between nanomaterial exposure and observed peripheral microvascular dysfunction. To test this hypothesis, wild-type C57B6J (WT) and TSP-1 knockout (KO) mice were exposed via lung aspiration to 50 μg MWCNT or a Sham dispersion medium control. Following exposure (24 h), arteriolar characteristics and reactivity were measured in the gluteus maximus muscle using intravital microscopy (IVM) coupled with microiontophoretic delivery of acetylcholine (ACh) or sodium nitroprusside (SNP). In WT mice exposed to MWCNT, skeletal muscle TSP-1 protein increased > fivefold compared to Sham exposed, and exhibited a 39% and 47% decrease in endothelium-dependent and -independent vasodilation, respectively. In contrast, TSP-1 protein was not increased following MWCNT exposure in KO mice and exhibited no loss in dilatory capacity. Microvascular leukocyte-endothelium interactions were measured by assessing leukocyte adhesion and rolling activity in third order venules. The WT + MWCNT group demonstrated 223% higher leukocyte rolling compared to the WT + Sham controls. TSP-1 KO animals exposed to MWCNT showed no differences from the WT + Sham control. These data provide evidence that TSP-1 is likely a central mediator of the systemic microvascular dysfunction that follows pulmonary MWCNT exposure.
authors.affiliation: a Division of Exercise Physiology , West Virginia University School of Medicine , Morgantown , WV , USA.
authors.forename: W Kyle
authors.initials: WK
authors.lastname: Mandler
authors.affiliation: b Department of Physiology and Pharmacology , West Virginia University School of Medicine , Morgantown , WV , USA.|c Center for Cardiovascular & Respiratory Sciences , West Virginia University, Robert C. Byrd Health Sciences Center , Morgantown , WV , USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Nurkiewicz
authors.affiliation: d National Institute for Occupational Safety and Health , Morgantown , WV , USA.
authors.forename: Dale W
authors.initials: DW
authors.lastname: Porter
authors.affiliation: a Division of Exercise Physiology , West Virginia University School of Medicine , Morgantown , WV , USA.|c Center for Cardiovascular & Respiratory Sciences , West Virginia University, Robert C. Byrd Health Sciences Center , Morgantown , WV , USA.
authors.forename: I Mark
authors.initials: IM
authors.lastname: Olfert
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D036904:Leukocyte Rolling / Q000187:drug effects; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D037742:Nanotubes, Carbon / Q000737:chemistry / Q000633:toxicity*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects* / Q000235:genetics
chemical_list: D037742:Nanotubes, Carbon; D019700:Thrombospondin 1
keywords: Inflammation; endothelial dysfunction; microvascular dysfunction; nitric oxide