ESTROGEN--BONE BLOOD FLOW AND BONE MECHANICAL PROPERTIES

骨质疏松症和妇女骨折的高发率是一个重大的公共卫生问题。在老年妇女中，骨质流失的速度与血流量的减少有关，这表明骨血流量的减少有助于骨质疏松症的发生。本研究将验证骨血流量随年龄减少是由于雌激素水平降低导致血管内皮功能失调的假设。我们提出以下观点：随着女性雌激素水平随着年龄的增长而下降，骨血管内皮细胞功能下降，骨小动脉对生理性收缩刺激的反应更强，导致骨血流量减少，随后骨密度下降。这一假设将通过评估年轻（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验证，雌性大鼠接受或未接受雌激素治疗。骨血管内皮细胞的功能将与以下因素相关：(1)基础骨血流，(2)骨血管收缩反应性，(3)血浆雌激素水平，(4)骨生物力学特性。具体目的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。具体目的#2是评估相同三个年龄的雌性大鼠骨小动脉的血管收缩反应性，在去除内皮之前和之后，评估内皮在收缩剂的作用下产生扩张产物的能力。具体目的#3是确定雌激素治疗是否会保护衰老雌性大鼠的血管内皮细胞功能、基础骨血流量、血管反应性和骨力学性能。具体目的#4是确定雌激素是否通过增加骨血管中一氧化氮合酶的表达来改善内皮细胞功能。

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.