Endothelial Transduction of Shear Stress

本研究的目标是更好地理解内皮细胞如何将物理力（剪切应力）转化为化学信号（一氧化氮，NO）。内皮细胞中剪切依赖性NO的产生在许多血管床中都有很好的特征。然而，潜在的。一氧化氮形成的机制尚未完全确定。此外，在某些机制表征的情况下，内皮细胞来源和/或所采用的剪切应力刺激使结果与体内层流环境无关，而体内层流环境对血管张力的依赖贡献至关重要。初步证据表明，内皮细胞K+通道在剪应力增加的情况下被激活，这可能有助于膜超极化和NO的形成。在剪应力升高后也观察到[Ca2+]的增加，但Ca2+的来源/途径尚不清楚。因此，本提案的具体目的是：1)确定离子通道在剪切诱导的Ca2+依赖性NO生成中的作用，以及2)研究由NO形成引发的剪切依赖性内皮反应的潜在途径。总的来说，这些实验将增强我们对剪切应力下内皮NO形成的细胞机制的理解，并为未来可能开发新的药物/策略治疗心血管疾病（如高血压）的研究奠定基础。

The goal of this proposal is to better understand how an endothelial cell transduces a physical force (shear stress) into a chemical signal (nitric oxide, NO). Shear-dependent production of NO in endothelial cells is well characterized in numerous vascular beds. However, the underlying .mechanisms by which NO is formed are not completely defined. Furthermore, in some cases where mechanisms are characterized, the endothelial cell source and/or the shear stress stimulus employed render the results irrelevant to the in vivo laminar flow environment where flow- dependent contributions to vascular tone are vital. Preliminary evidence suggests that endothelial K+ channels are activated in response to increased shear stress, which may contribute to membrane hyperpolarization and NO formation. Increases in [Ca2+], are also observed after raising shear stress, but the Ca2+ source/pathway is not well understood. Therefore, the specific aims of this proposal are to: 1) determine the role of ion channels in shear induced Ca2+-dependent NO production, and 2) investigate potential pathways initiated by NO formation that contribute to the shear-dependent endothelial response. Collectively, these experiments will enhance our understanding of cellular mechanisms by which endothelial NO is formed during shear stress, and contribute to the foundation for future studies that may develop new pharmacological agents/strategies to treat cardiovascular diseases such as hypertension.