大鼠骨阻力动脉对甲状旁腺激素1-84、甲状旁腺激素1-34和甲状旁腺激素相关蛋白1-34的血管舒张机制。
Mechanisms of vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34 in rat bone resistance arteries.
作者信息
Benson T, Menezes T, Campbell J, Bice A, Hood B, Prisby R
机构信息
Department of Kinesiology, University of Texas at Arlington, Arlington, TX, 76019, USA.
Bone Vascular and Microcirculation Laboratory, Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, 19713, USA.
出版信息
Osteoporos Int. 2016 May;27(5):1817-26. doi: 10.1007/s00198-015-3460-z. Epub 2016 Jan 5.
UNLABELLED
Parathyroid hormone (PTH) augments bone metabolism and bone mass when given intermittently. Enhanced blood flow is requisite to support high tissue metabolism. The bone arteries are responsive to all three PTH analogs, which may serve to augment skeletal blood flow during intermittent PTH administration.
INTRODUCTION
PTH augments bone metabolism. Yet, mechanisms by which PTH regulates bone blood vessels are unknown. We deciphered (1) endothelium-dependent and endothelium-independent vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34, (2) the signaling pathways (i.e., endothelial nitric oxide synthase [eNOS], cyclooxygenase [COX], protein kinase C [PKC], and protein kinase A [PKA]), and (3) receptor activation.
METHODS
Femoral principal nutrient arteries (PNAs) were given cumulative doses (10(-13)-10(-8) M) of PTH 1-84, PTH 1-34, and PTHrP 1-34 with and without signaling pathway blockade. Vasodilation was also determined following endothelial cell removal (i.e., denudation), PTH 1 receptor (PTH1R) inhibition and to sodium nitroprusside (SNP; a nitric oxide [NO] donor).
RESULTS
Vasodilation was lowest to PTH 1-34, and maximal dilation was highest to PTHrP 1-34. Inhibition of eNOS reduced vasodilation to PTH 1-84 (-80 %), PTH 1-34 (-66 %), and PTHrP 1-34 (-48 %), evidencing the contribution of NO. Vasodilation following denudation was eliminated (PTH 1-84 and PTHrP 1-34) and impaired (PTH 1-34, 17 % of maximum), highlighting the importance of endothelial cells for PTH signaling. Denuded and intact PNAs responded similarly to SNP. Both PKA and PKC inhibition diminished vasodilation in all three analogs to varying degrees. PTH1R blockade reduced vasodilation to 1, 12, and 12 % to PTH 1-84, PTH 1-34, and PTHrP 1-34, respectively.
CONCLUSIONS
Vasodilation of femoral PNAs to the PTH analogs occurred via activation of the endothelial cell PTH1R for NO-mediated events. PTH 1-84 and PTHrP 1-34 primarily stimulated PKA signaling, and PTH 1-34 equally stimulated PKA and PKC signaling.
未标记
间歇性给予甲状旁腺激素（PTH）可增强骨代谢和骨量。增强的血流是支持高组织代谢所必需的。骨动脉对所有三种PTH类似物均有反应，这可能有助于在间歇性给予PTH期间增加骨骼血流。
引言
PTH可增强骨代谢。然而，PTH调节骨血管的机制尚不清楚。我们解析了（1）PTH 1-84、PTH 1-34和PTHrP 1-34的内皮依赖性和非内皮依赖性血管舒张，（2）信号通路（即内皮型一氧化氮合酶[eNOS]、环氧化酶[COX]、蛋白激酶C[PKC]和蛋白激酶A[PKA]），以及（3）受体激活。
方法
给股骨干主要营养动脉（PNA）累积给予剂量为10^(-13)-10^(-8) M的PTH 1-84、PTH 1-34和PTHrP 1-34，同时或不进行信号通路阻断。在内皮细胞去除（即剥脱）、PTH 1受体（PTH1R）抑制以及给予硝普钠（SNP；一种一氧化氮[NO]供体）后，也测定血管舒张情况。
结果
PTH 1-34引起的血管舒张最低，而PTHrP 1-34引起的最大舒张最高。抑制eNOS可降低PTH 1-84（-80%）、PTH 1-34（-66%）和PTHrP 1-34（-48%）引起的血管舒张，证明了NO的作用。剥脱后PTH 1-84和PTHrP 1-34引起的血管舒张消失，PTH 1-34引起的血管舒张受损（为最大值的17%），突出了内皮细胞对PTH信号传导的重要性。剥脱和完整的PNA对SNP的反应相似。PKA和PKC抑制均不同程度地降低了所有三种类似物引起的血管舒张。PTH1R阻断分别将PTH 1-84、PTH 1-34和PTHrP 1-34引起的血管舒张降低至1%、12%和12%。
结论
股骨干PNA对PTH类似物的血管舒张是通过激活内皮细胞PTH1R介导NO介导的事件而发生的。PTH 1-84和PTHrP 1-34主要刺激PKA信号传导，而PTH 1-3,4同等程度地刺激PKA和PKC信号传导。
Zotero 插件