Identifying A Skeleton-Derived Factor for Vascular Aging

识别血管老化的骨骼衍生因子

• 批准号: 10544756
• 负责人: Mei Wan
• 金额: $ 47.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544756
• 关键词: Ablation; Acceleration; Acute; Age; Aging; Angiogenic Factor; Animals; Aorta; Attenuated; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Bone Density; Bone Marrow; Bone Marrow Transplantation; Bone Resorption; Brain; CDKN2A gene; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell Lineage; Cell secretion; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Clinical; Clinical Research; Data; Dementia; Development; Distal; Elderly; Endocrine Glands; Event; Exposure to; Genetic; Goals; Health; Homeostasis; Hormonal; Image; Impairment; Incidence; Infusion procedures; Knockout Mice; Link; Longitudinal Studies; Macrophage; Macrophage Colony-Stimulating Factor; Mediating; Mononuclear; Morbidity - disease rate; Mus; Neurodegenerative Disorders; Nuclear; Organ; Osteoclasts; Osteoporosis; Parabiosis; Pathologic; Patients; Peripheral; Phenotype; Physiological; Physiology; Plasma; Population; Positioning Attribute; Reporter; Risk Factors; Role; Serum; Skeleton; Source; TNFSF11 gene; Techniques; Testing; Tissues; Transgenic Mice; Vascular System; White Matter Disease; Work; aged; arterial stiffness; bone; bone age; bone metabolism; calcification; cell type; cerebral capillary; cerebrovascular; cerebrovascular pathology; cognitive change; conditional knockout; defined contribution; density; disability; experimental study; human subject; monocyte; mortality; mouse model; novel; platelet-derived growth factor BB; public health relevance; response; senescence; skeletal

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.

摘要/总结 心脑血管疾病是导致死亡和残疾的主要原因，尤其是在 老年人口。越来越多的证据表明，来自远端器官的循环促衰老因子 加剧血管系统的老化。特别是，骨代谢与骨代谢之间存在联系。 脉管系统。临床研究表明，骨质疏松症与血管疾病之间存在反向、独立的相关性。 事件，例如主动脉硬化和脑血管疾病。因此，骨-血管相互作用可能 涉及心脑血管系统衰老的机制。我们的目标是确定 骨骼衍生因子通过血液循环加速血管老化。我们最近发现旧 动物血清中血管生成因子 PDGF-BB 水平升高，主动脉僵硬度增加， 与年轻小鼠相比，脑毛细血管的密度和完整性降低。重要的是，老年人的急性输注 将血浆注入年轻小鼠体内会导致血清 PDGF-BB 浓度升高，并导致类似的脑血管疾病 在老年小鼠中观察到的表型。我们之前发现，骨/骨髓中的前破骨细胞（Pre-OCs）是一种 分泌 PDGF-BB 的主要细胞类型。我们的初步数据表明 Pre-OCs 经历细胞衰老并 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PDGF-BB升高的主要来源。 PDGF-BB 维持体内稳态 生理条件下的血管系统，异常高浓度的PDGF-BB可能会导致血管 损害。我们的中心假设是，骨骼衍生的 PDGF-BB 是一种系统性促衰老因子， 加剧动脉硬化和脑血管功能障碍。在目标1中，我们将确立PDGF-BB的作用 作为通过血浆转移和异种共生加剧血管老化的全身因素 研究检查年轻小鼠是否会出现与年龄相关的主动脉和脑血管表型 暴露于老年小鼠或 Pdgfb 转基因小鼠的血液。在目标 2 中，我们将定义以下贡献： 通过骨髓移植实验研究衰老的Pre-OCs对血管老化的影响。我们也会测试 如果消融前 OC 或抑制前 OC 衰老可以挽救主动脉和脑血管 老年小鼠的病理。积极的发现将揭示骨骼细胞调节血管的机制 衰老，将为心血管和心血管疾病的治疗提供一条非常规但有前途的途径 脑血管疾病。