ESTROGEN--BONE BLOOD FLOW AND BONE MECHANICAL PROPERTIES

妇女骨质疏松症和骨折发病率高是一个重大的公共卫生问题。在老年妇女中，骨丢失率与血流量下降相关，这表明骨血流量减少有助于骨质疏松症的发展。本研究将检验骨血流量随年龄增长而减少是由于雌激素水平降低导致血管内皮功能障碍的假设。我们建议如下：随着女性雌激素水平随年龄的增长而降低，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，导致骨血流减少，随后骨密度降低。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（用雌激素处理或未处理）的骨血管内皮细胞功能来检验这一假设。骨血管内皮细胞功能将与：（1）基础骨血流量，（2）骨血管收缩反应性，（3）血浆雌激素水平，和（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。具体目的#2是评估在去除内皮之前和之后，来自相同三个年龄的雌性大鼠的骨小动脉的血管收缩反应性，以评价内皮响应收缩激动剂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护老龄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血管系统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.