Mechanosensation in vascular endothelium: the role of purinergic signalling

动脉的内腔由单层内皮内衬，单层内皮与血流的剪切机械力直接接触。内皮需要感知和响应这些力（血流）的变化，并释放改变血管张力的信号分子，调节局部组织灌注和全身血压。内皮中剪切力检测的分子基础定义不明确，但可能代表缺血后血压和血管重塑调节的重要药物靶点。哺乳动物细胞在轻微的机械刺激下可以生理性地释放ATP，尽管细胞释放途径仍然存在争议。细胞外ATP的生物学效应由激活嘌呤能受体（P2 Y，代谢型; P2 X离子型）介导。本项目将研究血管内皮细胞中流量依赖性ATP释放的分子机制，以及嘌呤能受体信号产生血管舒张分子并影响血管张力的后续途径。该项目将涉及血管生物学和药理学尖端技术的培训，包括压力肌造影术、钙成像、慢病毒生产和输送、细胞生物成像、流动条件和人体组织工作。

The lumen of arteries is lined by a monolayer of endothelium which is in direct contact with the shearing mechanical force of blood flow. The endothelium needs to sense and respond to changes in such forces (blood flow) and release signalling molecules that alter vascular tone, modulating local tissue perfusion and systemic blood pressure. The molecular basis for shear force detection in endothelium is poorly defined yet may represent an important drug target for the modulation of blood pressure and vascular remodeling following ischemia. ATP can be physiologically released by mammalian cells following mild mechanical stimulation, though the cellular release routes remain controversial. The biological effects of extracellular ATP are mediated by activation purinergic receptors (P2Y, metabotropic; P2X ionotropic). This project will investigate the molecular mechanisms underlying flow-dependent ATP release in vascular endothelium and the subsequent pathways through which purinergic receptors signal to produce vasodilatory molecules and influence vascular tone. The project will involve training in cutting-edge techniques in vascular biology and pharmacology including pressure myography, calcium imaging, lentivirus production and delivery, cellular bioimaging conditions of flow and work with human tissue.