Endothelial Transduction of Shear Stress

这项提议的目标是更好地理解内皮细胞如何将物理力(剪切力)转化为化学信号(一氧化氮，NO)。在许多血管床中，内皮细胞产生的NO依赖于剪切力。然而，形成NO的潜在机制还没有完全定义。此外，在某些机制已确定的情况下，内皮细胞来源和/或所采用的剪应力刺激使得结果与体内层流环境无关，在体内层流环境中，血流依赖对血管张力的贡献至关重要。初步证据表明，内皮细胞K+通道在剪切力增加时被激活，这可能是膜超极化和NO形成的原因。在增加切应力后，也可以观察到[Ca~(2+)]的增加，但对Ca~(2+)的来源/途径尚不清楚。因此，这项建议的具体目的是：1)确定离子通道在剪切诱导的钙依赖性NO产生中的作用，以及2)研究NO形成启动的有助于剪切依赖性内皮反应的潜在途径。总之，这些实验将加深我们对剪切力中内皮NO形成的细胞机制的理解，并为未来可能开发新的药理药物/策略来治疗高血压等心血管疾病的研究奠定基础。

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.