Endothelial Transduction of Shear Stress

该提案的目标是更好地了解内皮细胞如何将物理力（剪切应力）转换为化学信号（一氧化氮，NO）。内皮细胞中NO的剪切依赖性产生在许多血管床中得到很好的表征。然而，NO形成的潜在机制并不完全清楚。此外，在表征机制的一些情况下，所采用的内皮细胞源和/或剪切应力刺激使得结果与体内层流环境无关，其中对血管张力的流动依赖性贡献是至关重要的。初步证据表明，内皮K+通道被激活，以响应增加的剪切应力，这可能有助于膜超极化和NO的形成。在提高剪切应力后也观察到[Ca 2 +]增加，但Ca 2+来源/途径尚不清楚。因此，本提案的具体目标是：1）确定离子通道在剪切诱导的Ca 2+依赖性NO产生中的作用，以及2）研究由NO形成引发的有助于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内皮NO在剪切应力过程中形成的细胞机制的理解，并为未来可能开发新的药理学药物/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.