Abstract 324: Tumor Necrosis Factor-a (TNF-a) Mediates Microvascular Dysfunction Induced by High-fat Diet and Murine Cytomegalovirus (mCMV) Infection in a Mouse Model

Abstract

Cardiovascular diseases are mediated by a variety of risk factors, e.g. obesity and infections. Complicated obesity and mCMV each induce microvascular dysfunction in mouse models. However, the impact of mild obesity on microvascular homeostasis and its possible synergism with cytomegalovirus infection remain unclear. We have shown that 8 wks high-fat diet (HFD) increases leukocyte recruitment in cremasteric post-capillary venules, and mCMV accelerates and sustains this response. We hypothesized that HFD and/or mCMV impair phenylephrine-mediated vasoconstriction in arterioles, and that the arteriolar and venular responses are mediated by an imbalance between TNF-α and leptin, vs. adiponectin. Mice were inoculated with mock or mCMV and at 4 wks post-infection (pi) started on HFD or left on normal diet (ND). At 12 wks pi, leukocyte recruitment and arteriolar vasoconstriction were assessed by intravital microscopy. Adiponectin and leptin were measured by ELISA. Some mice were treated with anti-TNF-α antibodies 2 days prior to observation. mCMV infection alone did not alter any parameter when compared to Mock-ND. Arteriolar vasoconstriction to phenylephrine was impaired in both HFD groups vs. Mock-ND mice. TNF-α inhibition partially restored this impaired vasoconstriction. Leukocyte adhesion was increased in both HFD groups vs. ND mice, and was ameliorated by anti-TNF-α antibody treatment in mCMV-HFD, but not Mock-HFD mice. Adiponectin levels in HFD vs. ND groups were slightly increased, and leptin levels were ~5-6-fold higher. Our results suggest that HFD-/+mCMV infection impairs arteriolar vasoconstriction via a TNF-α dependent mechanism. TNF-α independent HFD-induced leukocyte adhesion in venules is changed to a TNF-α dependent pathway by mCMV infection. Increased leptin levels in HFD groups correlate with previous findings linking obesity and increased leptin. Increased adiponectin levels in HFD animals are contrary to responses previously reported for complicated obesity and may represent an initial compensatory role for adiponectin in the response to HFD-induced weight gain and inflammation. However, the roles for leptin and adiponectin require future investigation.