Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice.
The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel, 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 Ca(2+) 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.
Yamamoto
Kimiko
K
Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Sokabe
Takaaki
T
Matsumoto
Takahiro
T
Yoshimura
Kimihiro
K
Shibata
Masahiro
M
Ohura
Norihiko
N
Fukuda
Toru
T
Sato
Takashi
T
Sekine
Keisuke
K
Kato
Shigeaki
S
Isshiki
Masashi
M
Fujita
Toshiro
T
Kobayashi
Mikio
M
Kawamura
Koichi
K
Masuda
Hirotake
H
Kamiya
Akira
A
Ando
Joji
J
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D001808:Blood Vessels / Q000473:pathology; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008638:Mesenteric Arteries / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4; D012039:Regional Blood Flow; D013997:Time Factors
C548227:P2rx4 protein, mouse; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D000109:Acetylcholine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester