Identifying A Skeleton-Derived Factor for Vascular Aging

识别血管老化的骨骼衍生因子

• 批准号: 10202909
• 负责人: Mei Wan
• 金额: $ 49.12万
• 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/10202909
• 关键词: Ablation; Acute; Age; Aging; Angiogenic Factor; Animals; Aorta; Attenuated; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Bone Density; Bone Marrow; Bone Marrow Transplantation; Brain; CDKN2A gene; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell Lineage; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Clinical; Clinical Research; Cross-Sectional Studies; Data; Dementia; Development; Distal; Elderly; Endocrine Glands; Event; Exposure to; Genetic; Goals; Health; Homeostasis; Hormonal; Image; Impairment; Incidence; Infusion procedures; Knockout Mice; Lead; Link; Longitudinal Studies; Macrophage Colony-Stimulating Factor; Mediating; Mononuclear; Morbidity - disease rate; Mus; Neurodegenerative Disorders; Organ; Osteoclasts; Osteoporosis; Parabiosis; Pathologic; Patients; Peripheral; Phenotype; Physiological; Physiology; Plasma; Population; Positioning Attribute; Reporter; Risk Factors; Role; Serum; Skeleton; Source; Structure; 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; macrophage; 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.

抽象/总结