Endothelial Dysfunction With Nano‐Silica Oxide Exposure Differs In Diabetic Vs. Old Mice

Our purpose was to determine whether aspiration exposure to nano‐metal oxides caused endothelial dysfunction (ED) in diabetic or older C57 mice. Previously, we have shown that mild to moderate ED is induced in young healthy C57 mice (~100d). C57 male mice (Old, 308±18d, 41±4g, 198±40mg/dl blood glucose, N=11) and db/db male mice (Db, 144±6 d, 43±4 g, 186±33, N=6) were anesthetized (isoflurane) and aspirated 100µl containing 20µg of nano‐silica (S) or vehicle (V, saline with 0.1% albumin). The next day, OldV mice gained 0.6±0.6g while treatment mice lost weight (OldS ‐2±2, DbS ‐0.9±0.8). Bronchial alveolar lavage in OldV was 5820±3000cells/ml and increased 8.8‐fold (OldS); lung wet/dry weight increased 25±3% (DbS). Using intravital microscopy, arterioles (mesenteric ~130µm dia., cremaster ~50μm) were observed. Adenosine (10‐4M ea) dilation was significantly attenuated in the OldV compared to young mice, or DbV mice, and further attenuated in DbS mice. ED was tested by dose response to bradykinin (BK, 10‐8‐10‐5M), acetylcholine (ACH, 10‐7‐10‐4M), isoproterenol (ISO, 10‐14‐10‐4M). Peak dilation was attenuated to all three agonists to varying extents due to age and further due to exposure to S. Low dose ISO induced a significant dilation with exposure to S (not age); this behavior is consistent with an inflammatory process. ED is present in older mice and in young db/db mice. Further dysfunction is induced with exposure to nano‐silica that uncovers low dose dilation to isoproterenol. Thus it is suggested that the inflammatory process induced by exposure to metal oxides includes clinical signs of inflammation and altered beta‐adrenergic receptor recycling. NIH DK68401 AHA 0655908T