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.

Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα‐ and NOX2‐dependent pathway

“…Importantly, TSP-1 can inhibit endothelial nitric oxide synthase (eNOS) activation and thus reduce NO production (Isenberg, Martin-Manso, Maxhimer, & Roberts, 2009). Furthermore, TSP-1 has a direct role in mediating immune infiltration (Mandler, Nurkiewicz, Porter, & Olfert, 2017), a key source of tissue inflammation. However, TSP-1 expression can also be mediated by TNF signalling (Fairaq, Goc, Artham, Sabbineni, & Somanath, 2015), suggesting a role for TNF mediating TSP-1 production as a potential mechanism of tPVATmediated aortic dysfunction in MetS.…”

Susceptibility Factors in Chronic Lung Inflammatory Responses to Engineered Nanomaterials

“…Thrombospondin (TSP-1) is a protein involved in wound healing and regulating blood pressure [ 182 , 183 , 184 , 185 ]. TSP-1 binding to the cell surface receptor CD47 in vascular smooth muscles has been reported to inhibit endothelial nitric oxide synthase (eNOS) [ 182 , 186 ].…”

“…TSP-1 also has another receptor, CD36, that may also play a role in suppressing eNOS activity [ 183 ]. Thus, the impaired signaling axis of TSP-1/CD47/CD36 has been implicated in different cardiovascular diseases, including cardiac hypertrophy, impaired angiogenesis, and pulmonary hypertension [ 184 , 185 , 187 , 188 , 189 ]. Studies with Tsp1 KO mice and CD47 KO mice suggest that TSP-1 is critical to regulate endothelial function when exposed to ENMs [ 184 , 185 ].…”

“…Thus, the impaired signaling axis of TSP-1/CD47/CD36 has been implicated in different cardiovascular diseases, including cardiac hypertrophy, impaired angiogenesis, and pulmonary hypertension [ 184 , 185 , 187 , 188 , 189 ]. Studies with Tsp1 KO mice and CD47 KO mice suggest that TSP-1 is critical to regulate endothelial function when exposed to ENMs [ 184 , 185 ]. Two studies by Mandler et al showed that Tsp1 KO mice exposed to MWCNTs through oropharyngeal aspiration resulted in microvascular dysregulation that could play a critical role in developing cardiovascular diseases [ 184 , 185 ].…”

“…Studies with Tsp1 KO mice and CD47 KO mice suggest that TSP-1 is critical to regulate endothelial function when exposed to ENMs [ 184 , 185 ]. Two studies by Mandler et al showed that Tsp1 KO mice exposed to MWCNTs through oropharyngeal aspiration resulted in microvascular dysregulation that could play a critical role in developing cardiovascular diseases [ 184 , 185 ]. This finding suggested that impairment of TSP-1 is critical to cardiovascular function and leads to greater susceptibility to severe cardiovascular disorders upon exposure to MWCNTs.…”