ESTROGEN--BONE BLOOD FLOW AND BONE MECHANICAL PROPERTIES

雌激素--骨血流量和骨机械特性

• 批准号: 6012597
• 负责人: JOHN T FLEMING
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6012597
• 关键词: acetylcholine; age difference; aging; animal old age; arterioles; biomechanics; bone; bone density; disease /disorder model; estrogens; female; gene expression; hormone therapy; laboratory rat; mechanical stress; musculoskeletal circulation; nitric oxide synthase; nonhuman therapy evaluation; norepinephrine; osteoporosis; ovariectomy; vascular endothelium; vasoconstriction; vasodilatation; vasodilation

Osteoporosis and the high incidence of bone fractures among women is a major public health issue. Among aged women, the rate of bone lose has been correlated with a decline in blood flow, suggesting that a decrease in bone blood flow contributes to the development of osteoporosis. This study will test the hypothesis that the decrease in bone blood flow with age is due to a dysfunctional vascular endothelium resulting from a decrease in estrogen levels. We propose the following: as estrogen level among females decrease with age, bone vascular endothelial cell function decreases, bone arterioles become more reactive to physiologic constrictor stimuli resulting in a decrease in bone blood flow and subsequently a decrease in bone density. This hypothesis will be tested by assessing bone vascular endothelial cell function among young (2 months), middle aged (5 months) and old (15 months) female rats, either treated or untreated with estrogen. Bone vascular endothelial cell function will be correlated with: (1) basal bone blood flow, (2) bone blood vessel vasoconstrictor reactivity, (3) plasma estrogen levels, and (4) bone biomechanical properties. Specific Aim #1 is to assess bone vascular endothelial cell function among female rats at three ages (2, 5 and 15 months). Specific Aim #2 is to assess the vasoconstrictor reactivity of bone arterioles from female rats at the same three ages, before and after removing the endothelium to evaluate the ability of the endothelium to produce dilator products in response to constrictor agonists. Specific Aim #3 is to determine if estrogen treatment will preserve vascular endothelial cell function, basal bone blood flow, vascular reactivity and bone mechanical properties among aging female rats. Specific Aim #4 is to determine if estrogen improves endothelial cell function by increasing the expression of nitric oxide synthase in the bone vasculature.

骨质疏松症和女性骨折的高发率是一个重大的公共卫生问题。在老年女性中，骨质流失的速度与血流量的下降相关，这表明骨血流量的减少会导致骨质疏松症的发生。这项研究将检验以下假设：随着年龄的增长，骨血流量减少是由于雌激素水平下降导致血管内皮功能障碍所致。我们提出以下建议：随着女性雌激素水平随着年龄的增长而降低，骨血管内皮细胞功能降低，骨小动脉对生理收缩刺激的反应性更强，导致骨血流量减少，从而导致骨密度降低。该假设将通过评估经过或未经过雌激素治疗的年轻（2个月）、中年（5个月）和老年（15个月）雌性大鼠的骨血管内皮细胞功能来检验。骨血管内皮细胞功能与：（1）基础骨血流量，（2）骨血管血管收缩反应性，​​（3）血浆雌激素水平，以及（4）骨生物力学特性相关。具体目标#1 是评估三个年龄（2、5 和 15 个月）雌性大鼠的骨血管内皮细胞功能。具体目标#2是评估相同三个年龄的雌性大鼠在去除内皮之前和之后的骨小动脉的血管收缩反应性，​​以评估内皮响应收缩激动剂而产生扩张产物的能力。具体目标#3是确定雌激素治疗是否会保留老年雌性大鼠的血管内皮细胞功能、基础骨血流量、血管反应性和骨机械特性。 具体目标#4是确定雌激素是否通过增加骨脉管系统中一氧化氮合酶的表达来改善内皮细胞功能。

项目成果

Bone medullary arterioles from ovariectomized rats have smaller baseline diameters but normal eNOS expression and NO-mediated dilation.

卵巢切除大鼠的骨髓小动脉具有较小的基线直径，但 eNOS 表达和 NO 介导的扩张正常。

• DOI: 10.1016/j.lfs.2004.10.083
• 发表时间: 2005
• 期刊: Life sciences.
• 作者: Soukhova-O'Hare,Galia;Lei,Zhenmin;Falcone,JeffC;Barati,MichelleT;Feitelson,JeremyBA;Rao,ChV;Fleming,JohnT
• 通讯作者: Fleming,JohnT