Yamamoto Kimiko, Ando Joji
Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Yakugaku Zasshi. 2010 Nov;130(11):1407-11. doi: 10.1248/yakushi.130.1407.
The structure and function of blood vessels adapt to environmental changes, for example, physical development and exercise. This phenomenon is based on the ability of endothelial cells (ECs) to sense and respond to blood flow. ECs are in direct contact with blood flow and exposed to shear stress. A number of recent studies have revealed that ECs recognize changes in shear stress and transmit signals to the interior of the cell, which leads to cellular responses that involve changes in cell morphology, cell function, and gene expression. Cultured human pulmonary artery ECs (HPAECs) showed Ca²(+) influx via an ATP-operated cation channel, P2X4, in response to shear stress. We have recently found that shear-induced activation of P2X4 requires endogenously released ATP and that shear stress induced HPAECs to release ATP, which was mediated by cell-surface ATP synthase located in caveolae. To gain insight into its significance, we generated a P2X4-deficient mouse. P2X4(-/-) mice do not exhibit normal EC responses to flow, such as Ca²(+) influx and subsequent production of NO, a potent vasodilator. Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2X4(-/-) mice. Furthermore, P2X4(-/-) mice have higher blood pressure than wild-type mice. Moreover, no adaptive vascular remodeling is observed in the P2X4(-/-) mice. Thus, P2X4-mediated shear stress mechanotransduction plays an important role in the vascular homeostasis, including the control of blood pressure and vascular remodeling.
血管的结构和功能会适应环境变化，例如身体发育和运动。这种现象基于内皮细胞（ECs）感知和响应血流的能力。内皮细胞与血流直接接触并受到剪切应力的作用。最近的一些研究表明，内皮细胞能够识别剪切应力的变化并将信号传递到细胞内部，从而引发涉及细胞形态、细胞功能和基因表达变化的细胞反应。培养的人肺动脉内皮细胞（HPAECs）在受到剪切应力时，通过一种ATP门控阳离子通道P2X4出现Ca²⁺内流。我们最近发现，剪切力诱导的P2X4激活需要内源性释放的ATP，并且剪切应力诱导HPAECs释放ATP，这是由位于小窝中的细胞表面ATP合酶介导的。为了深入了解其重要性，我们培育了一种P2X4基因缺陷小鼠。P2X4基因敲除（-/-）小鼠对血流的内皮细胞正常反应缺失，如Ca²⁺内流以及随后强效血管舒张剂一氧化氮（NO）的产生。此外，在P2X4基因敲除（-/-）小鼠中，由急性血流增加诱导的血管扩张明显受到抑制。此外，P2X4基因敲除（-/-）小鼠的血压高于野生型小鼠。而且，在P2X4基因敲除（-/-）小鼠中未观察到适应性血管重塑。因此，P2X4介导的剪切应力机械转导在血管稳态中发挥重要作用，包括血压控制和血管重塑。
