Abstract 355: Endothelial S100A1 Modulates Vascular Function via Nitric Oxide
Background- S100A1, a Ca2+ binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca2+-handling in neurons, skeletal muscle and cardiac muscle. Since eNOS activation is classically dependent on an increase in intracellular Calcium transients [Ca2+]i and S100A1 expression was recently described in EC, we sought to investigate the impact of endothelial S100A1 on the regulation of endothelial and vascular function.
Methods and Results- Thoracic aortas from S100A1 knock-out mice (SKO) showed significantly reduced relaxation in response to acetylcholine (Ach) compared to wild-type (WT) aortas while direct vessel relaxation using sodium nitroprusside was unaltered. Endothelial dysfunction translated into significantly increased systolic (149.4±6.6 mmHg vs. 120.4±4.2 mmHg, p<0.05) and diastolic blood pressure in SKO (n=7) compared to WT (n=6) in vivo. Mechanistically, both, basal (477.5±64.4 nM/mg tissue vs. 946.5±82.6 nM/mg tissue; p<0.05) and Ach-induced endothelial NO release of SKO aortas were significantly reduced compared to WT. Impaired endothelial NO production in SKO could be, at least in part, attributed to diminished intracellular Ca2+-transients [Ca2+]i in EC in response to Ach (10−5 M). Importantly, reduced [Ca2+]i in SKO-derived EC could be normalized by adenoviral-mediated S100A1 expression. Moreover, S100A1 over-expression in EC further increased NO generation which could be blocked by the IP3-receptor blocker 2-aminoethoxydiphenylborate. Finally, catecholamines and hormones up-regulated in heart failure (HF) were found to reduce S100A1 expression in vitro.
Conclusions- Endothelial S100A1 critically modulates vascular function since lack of S100A1 expression in EC leads to decreased [Ca2+]i and endothelial NO release, which at least contributes to impaired endothelium-dependent vascular relaxation and increased blood pressure in SKO mice. Targeting endothelial S100A1 expression might therefore be a novel therapeutic means to improve endothelial function in vascular disease or HF.