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/摘要 心血管和脑血管疾病是死亡和残疾的主要原因，尤其是在 老年人。积累的证据表明，源自远端器官的循环促进因子 加剧血管系统的衰老。特别是，骨骼代谢与 脉管系统。临床研究表明骨质疏松与血管之间存在逆，独立的相关性 事件，例如主动脉僵硬和脑血管疾病。因此，骨血管相互作用可能 涉及心血管和脑血管系统衰老的基础机制。我们的目标是确定 骨骼来源的因素通过血液循环加速血管衰老。我们最近发现那老 动物的血清生成因子PDGF-BB的血清水平升高，并发展出主动脉僵硬增加，并且 相对于年轻小鼠，脑毛细血管的密度和完整性降低。重要的是，急性输注老年 血浆中的年轻小鼠诱导血清PDGF-BB浓度和类似脑血管的升高 表型如在老年小鼠中所见。我们先前发现，骨/骨髓中的前骨前球菌（前OC）是一个 秘密PDGF-BB的主要细胞类型。我们的初步数据表明，前OC会经历细胞衰老和 分泌衰老期间大量的PDGF-BB。我们的结果表明，骨/骨髓中的前OC是一个 衰老期间循环pDGF-BB升高的主要来源。而PDGF-BB保持 在生理条件下的脉管系统，异常高浓度的PDGF-BB可能导致血管 损害。我们的核心假设是，骨骼衍生的PDGF-BB是一个系统性的因素 加剧动脉僵硬和脑血管功能障碍。在AIM 1中，我们将确定PDGF-BB的作用 作为通过进行血浆转移和异化抛物率加剧血管衰老的系统因素 研究年轻小鼠是否通过通过年龄相关主动脉和脑血管表型来 暴露于老年小鼠或PDGFB转基因小鼠的血液。在AIM 2中，我们将定义 通过进行骨髓移植实验，对血管衰老的衰老前oc。我们还将测试 如果前OC的消融或抑制前OC的衰老会挽救主动脉和脑血管 老年小鼠的病理。阳性发现将发现骨骼细胞调节血管的机制 衰老，并将为治疗心血管治疗和 脑血管疾病。