Identifying A Skeleton-Derived Factor for Vascular Aging

摘要/摘要 心脑血管疾病是导致死亡和残疾的主要原因，特别是在 老年人口。越来越多的证据表明，循环中的促衰老因子源自远端器官 加剧血管系统的老化。尤其是，骨骼新陈代谢和 脉管系统。临床研究表明，骨质疏松症与血管之间存在着反向的、独立的相关性 事件，如主动脉硬化和脑血管疾病。因此，骨-血管的相互作用很可能 涉及心脑血管系统衰老的潜在机制。我们的目标是找出 骨骼衍生因子，通过血液循环加速血管衰老。我们最近发现了一个古老的 动物血清中血管生成因子PDGF-BB水平升高，并出现主动脉僵硬和 与幼鼠相比，脑部毛细血管密度和完整性降低。重要的是，老年人的急性输液 幼年小鼠血浆诱导血清PDGF-BB浓度升高和类似脑血管病变 在老年小鼠中可见的表型。我们先前发现骨/骨髓中的破骨前细胞(Pre-OsteoCells，Pre-OCS)是一种 分泌PDGF-BB的主要细胞类型。我们的初步数据显示，前OCS经历了细胞衰老和 在衰老过程中分泌大量的PDGF-BB。我们的结果表明，骨/骨髓中的前OCS是一种 衰老过程中循环中PDGF-BB升高的主要来源。而PDGF-BB则维持细胞的动态平衡 血管系统在生理条件下，PDGF-BB浓度异常高可能导致血管 减损。我们的中心假设是骨骼来源的PDGF-BB是一种全身性促衰老因子 加重动脉硬化和脑血管功能障碍。在目标1中，我们将确定PDGF-BB的作用 作为一种全身性因素，通过传导血浆转移和异质共生来加剧血管老化 检测幼龄小鼠是否出现与年龄相关的主动脉和脑血管表型的研究 暴露于老龄小鼠或Pdgfb转基因小鼠的血液中。在目标2中，我们将定义 通过进行骨髓移植实验研究衰老前OCS对血管老化的影响。我们还将测试 如果消融前OCS或抑制前OCS的衰老可以挽救主动脉和脑血管 衰老小鼠的病理变化。积极的发现将揭示骨骼细胞调节血管的机制 这将为心血管疾病的治疗提供一条非传统但有希望的途径。 脑血管疾病。

ABSTRACT/SUMMARY Cardiovascular and cerebrovascular diseases are the leading causes of mortality and disability, especially in the elderly population. Accumulating evidence suggest that circulating pro-aging factors derived from distal organs exacerbate the aging of vascular system. Particularly, there is a link between bone metabolism and the vasculature. Clinical studies have shown an inverse, independent correlation between osteoporosis and vascular events, such as aortic stiffening and cerebrovascular disease. Therefore, the bone-vascular interplay likely involves mechanisms underlying the aging of cardiovascular and cerebrovascular system. Our goal is to identify skeleton-derived factors that accelerate vascular aging through blood circulation. We recently found that old animals have elevated serum level of angiogenesis factor PDGF-BB and develop increased aortic stiffness and reduced density and integrity of brain capillaries relative to young mice. Importantly, acute infusion of aged plasma into young mice induces an elevation in serum PDGF-BB concentration and a similar cerebrovascular phenotype as seen in aged mice. We previously found that pre-osteoclasts (Pre-OCs) in bone/bone marrow is a major cell type that secret PDGF-BB. Our preliminary data show that Pre-OCs undergo cellular senescence and secrete high amount of PDGF-BB during aging. Our results suggest that Pre-OCs in bone/bone marrow is a main source of elevated circulating PDGF-BB during aging. While PDGF-BB maintains the homeostasis of vasculature under physiological conditions, abnormally high concentration of PDGF-BB may lead to vascular impairment. Our central hypothesis is that skeleton-derived PDGF-BB is a systemic pro-aging factor to exacerbate arterial stiffening and cerebrovascular dysfunction. In Aim 1, we will establish the role of PDGF-BB as a systemic factor to exacerbate vascular aging by conducting plasma transfer and heterochonic parabiosis studies to examine whether young mice develop age-associated aortic and cerebrovascular phenotype by exposure to the blood of aged mice or Pdgfb transgenic mice. In Aim 2, we will define the contribution of senescent Pre-OCs to vascular aging by conducting bone marrow transplantation experiments. We will also test if ablation of Pre-OCs or inhibition of the senescence of Pre-OCs rescues the aortic and cerebrovascular pathologies in aged mice. Positive findings will uncover the mechanisms by which skeletal cells regulate vascular aging and will provide an unconventional but promising path for the treatment of cardiovascular and cerebrovascular diseases.