Ectonucleotidase modulation of age-dependent vascular calcification and stiffness

外切核苷酸酶调节年龄依赖性血管钙化和僵硬度

• 批准号: 10434038
• 负责人: Nadia Razaq Sutton
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-11-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434038
• 关键词: ADP Receptors; ATP Receptors; Achievement; Adenosine; Age; Age-Years; Aging; Agonist; Arteries; Atherosclerosis; Biological Process; Biology of Aging; Blood Vessels; Brain; C57BL/6 Mouse; Calcium; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell surface; Cells; Clinical; Coagulation Process; Collagen; Coronary artery; Cues; Data; Deposition; Development; Disease; Elasticity; Elastin; Elderly; Endothelial Cells; Environment; Enzymes; Exposure to; Extracellular Matrix; Fibrosis; Foundations; Future; Gene Expression; Healthcare; Heart; Human; Impairment; Inflammation; Inflammatory; Kidney; Knowledge; Leukocytes; Life; Longevity; Mediating; Metabolic; Mus; Organ; Osteogenesis; Pathologic; Patients; Phenotype; Physiologic pulse; Physiological; Play; Population; Process; Production; Proteins; Proteomics; Pulse Pressure; Purinergic P1 Receptors; Research; Research Personnel; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Stress; Stress Tests; Surface; Testing; Time; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; age related; aged; calcification; care burden; coronary artery calcification; demographics; experimental study; extracellular; human tissue; indexing; inflammatory marker; insight; middle age; mouse model; osteogenic; paracrine; prevent; radiological imaging; stem; transcription factor

Abstract With increasing age, blood vessels become stiffer and more calcified. In the latter years of the human lifespan, the process of vascular aging accelerates. The reason that blood vessels lose their youthful elasticity and ability to retard the deposition of calcium precipitously later in life is poorly understood. Ectonucleotidases are found on the surface of endothelial cells which line the inner surface of blood vessels, vascular smooth muscle cells, and leukocytes. The ectonucleotidase CD39 is responsible for cleaving ATP and ADP to form AMP, and subsequently, CD73 is responsible for generating adenosine from AMP. Since ATP and ADP are pro- inflammatory and act in a paracrine fashion, I hypothesize that ectonucleotidase activity plays a role in the vascular stiffness and calcification that occurs as a consequence of age. This is supported by my preliminary data in wild type (C57BL/6) mice, which demonstrates CD73 protein levels declined with age (up to 24 months) in the heart and kidney. This is also supported by preliminary data in mice and human tissues demonstrating that loss of CD73 expression promoted expression of the transcription factor Runx2, which is critical for osteogenesis. We hypothesize that loss of ectonucleotidase expression with age could have deleterious consequences on the vessel wall, resulting in an environment which promotes vascular calcification and stiffness. Since the role of ectonucleotidases in vascular aging is unknown, we will elucidate mechanisms which mediate age-dependent vascular calcification through the following aims. Aim 1: We will determine how age-dependent decline in vascular ectonucleotidase expression renders vessels susceptible to vascular calcification and fibrosis in a murine model. Aim 2: We will determine how ectonucleotidase activity mitigates arterial fibrosis and stiffness. Aim 3: We will determine if ectonucleotidase expression plays a role in age-driven human coronary artery calcification. Achievement of these aims will elucidate the role of ectonucleotidases in age-dependent vascular calcification and stiffness in mice and humans. The mechanistic insights obtained from these experiments will define my future investigative direction and serve as a foundation for a subsequent RO1 application as an independent investigator studying vascular biology and aging.

摘要