Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries.
Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries.
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DOI：
10.1161/atvbaha.108.171751
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Henrion D
中科院分区：
文献类型：
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作者：
Belin de Chantemèle EJ;Retailleau K;Pinaud F;Vessières E;Bocquet A;Guihot AL;Lemaire B;Domenga V;Baufreton C;Loufrani L;Joutel A;Henrion D
Notch3 是进化保守的 Notch 受体家族的成员，主要在血管平滑肌细胞中表达。人类和小鼠的遗传学研究揭示了 Notch3 通过调节动脉分化和出生后成熟，在远端阻力动脉的结构完整性中发挥着关键作用。我们使用动脉造影术研究了Notch3在从Notch3缺陷小鼠中分离出的小阻力血管（尾动脉和脑动脉）和大动脉（颈动脉）的血管张力中的作用。突变动脉的被动直径和顺应性没有改变。同样，去氧肾上腺素、KCl、血管紧张素 II 和血栓素 A2 的收缩以及乙酰胆碱或硝普钠的扩张不受影响。然而，Notch3 缺陷仅导致尾动脉和脑阻力动脉中与较高流量（剪切应力）介导的扩张相关的压力引起的肌原性张力显着降低。此外，在加压尾动脉中测量的 RhoA 活性和肌球蛋白轻链磷酸化在 Notch3KO 小鼠中显着降低。此外，Rho 激酶抑制剂 Y27632 对肌源性张力的抑制作用在突变尾动脉中减弱。 Notch3 通过调节 RhoA/Rho 激酶通路，在血管机械传导的控制中发挥重要作用，对阻力循环中的肌原张力和血流介导的扩张产生相反的影响。 Notch3 调节动脉分化和平滑肌细胞的出生后成熟。通过使用来自 Notch3 敲除小鼠的动脉，我们发现 Notch3 通过调节 RhoA/Rho 激酶途径（参与压力诱导（肌源性）张力），在控制阻力动脉机械传导中发挥重要作用。
Notch3, a member of the evolutionary conserved Notch receptor family, is primarily expressed in vascular smooth muscle cells. Genetic studies in human and mice revealed a critical role for Notch3 in the structural integrity of distal resistance arteries by regulating arterial differentiation and postnatal maturation. We investigated the role of Notch3 in vascular tone in small resistance vessels (tail and cerebral arteries) and large (carotid) arteries isolated from Notch3 deficient mice using arteriography. Passive diameter and compliance were unaltered in mutant arteries. Similarly, contractions to phenylephrine, KCl, angiotensin II and thromboxane A2 as well as dilation to acetylcholine or sodium nitroprusside were unaffected. However, Notch3 deficiency induced a dramatic reduction in pressure-induced myogenic tone associated with a higher flow (shear stress)-mediated dilation in tail and cerebral resistance arteries only. Furthermore, RhoA activity and myosin light chain phosphorylation, measured in pressurized tail arteries, were significantly reduced in Notch3KO mice. Additionally, myogenic tone inhibition by the Rho kinase inhibitor Y27632 was attenuated in mutant tail arteries. Notch3 plays an important role in the control of vascular mechano-transduction, by modulating the RhoA/Rho kinase pathway, with opposite effects on myogenic tone and flow-mediated dilation in the resistance circulation. Notch3 regulates arterial differentiation and postnatal maturation of smooth muscle cells. By using arteries from Notch3 knockout mice we found that Notch3 plays an important role in the control of resistance arteries mechano-transduction, by modulating the RhoA/Rho kinase pathway, which is involved in pressure-induced (myogenic) tone.