Abstract 17166: Homocysteine Modulates the Density and Composition of Myoendothelial Junctions
Hyperhomocysteinemia (HHcy) is a risk factor for macrovascular and neurovascular disease. HHcy also impairs the vasomotor function of microvessels though little is known of how homocysteine affects myoendothelial coupling. Plasminogen activator inhibitor-1 (PAI-1) regulates myoendothelial junction (MEJ) formation, while HHcy increases vascular PAI-1 expression. Using mice deficient in cystathionine beta-synthase (CBS+/−; a HHcy mouse model) and vascular cell co-/culture models, we tested the hypotheses that HHcy increases the density of microvascular myoendothelial junctions but decreases expression of connexin 43 and endothelial nitric oxide synthase (Cx43, eNOS), key players in cell-cell communication at the MEJ signaling domain. Transmission electron microscopy of arterioles in skeletal muscle demonstrated significantly more MEJs in HHcy vs wild type littermates (2.2±0.2 vs 5.1±0.3 MEJs per 10 μm, p<0.05). In a vascular cell co-culture model, Hcy reduced the expression of Cx43 (33 vs 92, n=2) and eNOS (12 vs 33, n=2) within MEJs as determined by western blot. Data also suggest that homocysteine treatment induces Cx43 phosphorylation on S368 (Cx43pS368/Cx43total ratio: 43±3 vs 64±14, n=3, p<0.05), which reduces functional communication through these channels. These studies suggest that HHcy may regulate heterocellular communication at the MEJ by modulating both the structure and functional composition of these signaling domains. These findings demonstrate a fundamentally new aspect of vascular dysregulation mediated by HHcy.
- © 2010 by American Heart Association, Inc.