Role of intermittent activation of parathyroid hormone receptor in exercise-induced vascular calcification

项目摘要/摘要 血管钙化，尤其是冠状动脉钙化(CAC)与高血压的风险增加有关。 心血管疾病，而有规律的体力活动与降低风险有关。因此，人们会 预测经常运动的人的CAC会更少，但临床研究表明情况正好相反。精英 运动员实际上比久坐不动的运动员有更多的CAC，尽管他们的心脏事件较少 费率。这项提议的目的是确定这一悖论的机制。临床研究表明 含有大量连续钙沉积的冠状动脉斑块与较少的心血管疾病有关 风险大于碎裂的钙沉积，一种可能性是运动将钙沉积重塑为一种 更稳定的微体系结构。理论分析模型还预测，减少的表面积 钙沉积有望降低斑块破裂风险。有趣的是，人类的一次运动 和小鼠导致甲状旁腺激素(PTH)短暂升高1.8倍，间歇性治疗 人和小鼠的甲状旁腺激素导致骨生长增加，这与血管的信号机制相同 钙化。我们最近的发现提供了甲状旁腺激素与血管微结构之间的联系 钙沉积，其中间歇性甲状旁腺素治疗减少了主动脉钙沉积的表面积 已存在血管钙化的高脂血症小鼠。我们的初步研究提供了更直接的 运动与血管钙沉积重塑的关系。我们发现高脂血症小鼠 在9周的跑步机上有预先存在的主动脉钙化的患者，血清甲状旁腺素水平升高， PTH受体在主动脉根部的水平，并减少矿物表面积通过核成像和 组织形态计量学。因此，我们假设运动通过激活血管中的PTH1受体， 将钙沉积物的微结构转变为更稳定的形式，降低了破裂风险。我们 将使用3个特定的目的来验证我们的假设，以确定：1)PTH1受体活性的丧失 阻断运动诱导的血管钙沉积重塑；2)循环的相对贡献 甲状旁腺素和局部(组织)甲状旁腺素相关肽(PTHrP)对运动诱导的微结构改变的影响； 3)混杂因素(性别、运动量、饮食和种类)对运动诱导的脑功能改变的影响 SMC转录组与血管钙沉积微结构。我们将使用药理学、遗传学、 和手术模型，终点将包括主动脉钙的进展和微结构 沉积物，包括基于结构分析的大小和表面积(系列18F-µPET/µCT， 组织形态计量学)、转录组分析和使用球囊导管的功能生物力学分析 一种机械断裂易损性传感器。这项拟议的研究意义重大，因为它将确定 大强度运动增加的血管钙化是保护还是有害，以及其影响 可以通过调节甲状旁腺素受体的激活来控制。

PROJECT SUMMARY/ABSTRACT Vascular calcification, especially coronary artery calcification (CAC), is associated with increased risk of cardiovascular disease, whereas regular physical activity is associated with decreased risk. Thus, one would predict that physically active individuals would have less CAC, yet clinical studies show the opposite. Elite athletes actually have more CAC than their sedentary counterparts even though they have lower cardiac event rates. The objective of this proposal is to determine the mechanism of this paradox. As clinical studies show that coronary plaques containing large, contiguous calcium deposits are associated with less cardiovascular risk than fragmented calcium deposits, one possibility would be that exercise remodels calcium deposits into a more stable microarchitecture. Theoretical analytical modeling also predicts that decreased surface area of calcium deposits is expected to reduce plaque rupture risk. Interestingly, a single bout of exercise in humans and mice causes a transient 1.8-fold elevation of parathyroid hormone (PTH), and intermittent treatment of PTH in humans and mice causes increased bone growth, which shares signaling mechanisms with vascular calcification. Our recent findings provide an association between PTH and microarchitecture of vascular calcium deposits, where intermittent PTH treatment reduces the surface area of aortic calcium deposits in hyperlipidemic mice with pre-existing vascular calcification. Our preliminary studies provide a more direct association of exercise with the remodeling of vascular calcium deposits. We found that hyperlipidemic mice with pre-existing aortic calcification on a 9-week treadmill regimen had increased serum PTH levels, increased PTH receptor levels in the aortic roots, and decreased mineral surface area by nuclear imaging and histomorphometry. Thus, we hypothesize that exercise, through activation of the vascular PTH1 receptor, shifts the microarchitecture of calcium deposits toward a more stabilized form, reducing the rupture risk. We will test our hypothesis using 3 Specific Aims to determine: 1) whether loss of PTH1 receptor activation blocks the exercise-induced remodeling of vascular calcium deposits; 2) the relative contributions of circulating PTH and local (tissue) PTH related peptide (PTHrP) on the exercise-induced changes in microarchitecture; and 3) effects of confounding factors (sex, exercise dose, diet, and species) on exercise-induced changes in the SMC transcriptome and vascular calcium deposit microarchitecture. We will use pharmacologic, genetic, and surgical models, and the endpoints will include progression and microarchitecture of aortic calcium deposits, including size and surface area based on structural analyses (serial 18F-µPET/µCT, histomorphometry), transcriptome analysis, and functional biomechanical analyses using a balloon catheter as a mechanical sensor for rupture vulnerability. The proposed research is significant because it will determine whether increased vascular calcification with intense exercise is protective or harmful and whether the effects can be controlled by modulating PTH receptor activation.