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Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice

Abstract

The structure and function of blood vessels adapt to environmental changes such as physical development and exercise1,2,3. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow4,5,6; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel7,8, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4−/− mice do not have normal endothelial cell responses to flow, such as influx of Ca2+ and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4−/− mice. Furthermore, P2rx4−/− mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice. Moreover, no adaptive vascular remodeling, that is, a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4−/− mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.

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Figure 1: Impaired endothelial cell responses to flow in P2rx4−/− mice.
Figure 2: P2rx4 gene transfer rescued the impaired flow-induced influx of Ca2+ and production of NO in cultured endothelial cells from P2rx4−/− mice.
Figure 3: Impaired vasodilatory responses in P2rx4−/− mice.
Figure 4: P2rx4−/− mice show higher blood pressure with less production of NO and impaired blood flow–induced vascular remodeling.

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Acknowledgements

This study was partly supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and by a grant from the Japan Health Sciences Foundation. The authors are grateful to U. Chung and F. Kugimiya (Divisions of Tissue Engineering and Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo) for suggestions on technical issues in establishing of adenovirus vectors. We also thank Y. Sawada for technical assistance.

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Correspondence to Joji Ando.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Targeted disruption of the P2rx4 gene. (PDF 1425 kb)

Supplementary Fig. 2

Changes in arterial diameter in response to step increases in pressure in mesenteric artery segments isolated from P2rx4−/− and wild-type mice. (PDF 9358 kb)

Supplementary Fig. 3

Reduction in blood flow during left external carotid ligation. (PDF 1459 kb)

Supplementary Fig. 4

Shear stress–induced phosphorylation of protein kinases. (PDF 621 kb)

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Yamamoto, K., Sokabe, T., Matsumoto, T. et al. Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat Med 12, 133–137 (2006). https://doi.org/10.1038/nm1338

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