STEREOLOGY AND RHEOLOGY OF INTIMA DAMAGE AT BIFURICATION

分叉时内膜损伤的体视学和流变学

• 批准号: 3354923
• 负责人: JAMES G WALMSLEY
• 金额: $ 8.97万
• 依托单位: COLLEGE OF MEDICINE AT ROCKFORD
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-30 至 1988-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354923
• 关键词: antiatherogenic agent; aorta coarctation; atherosclerosis; biomechanics; calcium channel blockers; cardiovascular pharmacology; cerebral aneurysm; cerebral artery; cerebrovascular occlusions; computer graphics /printing; dietary lipid; disease /disorder model; electron microscopy; human tissue; hypertension; mechanical pressure; mechanical stress; morphology; pathogenic diet; scanning electron microscopy; subarachnoid hemorrhage; vascular endothelium; vascular smooth muscle; vasoconstriction; vasodilation

For specific hemodynamic stresses, the hypotheses to be tested are that (i) damage is more profound at cerebral artery bifurcations than in adjacent branches or at extracranial bifurcations and (ii) such damage is initiated from the intima. The architecture of cerebral artery bifurcations will be examined in rabbits with aortic coarctation hypertension, atherosclerosis, or carotid ligation and from human autopsies. The focus will be on young adult male rabbits with appropriate controls. Quantitative stereological methods will be employed in order to comment on the role of endothelium, smooth muscle (SM) and the internal elastic lamina (IEL) in possible mechanical weakness of the arterial wall leading to atherosclerosis and aneurysm formation. The specific aims related to the structure of arterial bifurcations and medial gaps are (a) determine the patterns and precise orientation of endothelial and SM cells (b) map out the distribution, location and sizes of fenestrations in the IEL (c) quantitate any differences in proportional composition of the bifurcation wall compared to non-branching segments (d) determine the arrangement and interrelationship among cellular and acellular components of the intima. These structural parameters will be compared depending on (I) location (II) pressure or flow and (III) the existence of related pathology (atherosclerosis or aneurysms). The human cerebral circulation has a very high incidence of medial defects, minute aneurysms, and saccular aneurysms which may rupture resulting in subarachnoid hemorrhage, and arterial spasm. It is felt that a combination of congenital and/or acquired factors might give rise to aneurysm formation and rupture but there is as yet no accepted etiology. Stehbens (1) states "further information pertaining to the degenerative changes and hemodynamic stresses at arterial forks is the prerequisite for a more detailed outline of the pathogenesis of cerebral aneurysms". Only a quantitative stereological approach with mechanical analysis can provide this information. Revelance of experimental studies will be enhanced since the pattern of the rabbit and human cerebral vessels is very similar. Considering the incidence, mortality and morbidity of subarachnoid hemorrhage, it is important to answer fundamental questions about initial changes in bifurcation architecture which could be precursors for the pathogenesis of cerebral aneurysms which could lead to reevaluation of risk factors. More than half of Americans die from cardiovascular diseases of which most are related to the atherosclerotic process and this process is primarily due to familial hypercholesterolemia in less than 5% of cases (2). Cholesterol fed rabbits will provide data on the deposition of fat at carotid, cerebral and ear bifurcations. Yet altered blood pressure and flow may provide insights into the multifactorial and synergistic alterations which cause intimal cushions to form at the lateral angles and other sites about bifurcations. The same factors which cause abnormal permeability in small cerebral vessels may be a factor in intimal changes of larger bifurcations. Furthermore, since calcium entry blockers may have a protective effect against endothelial and SM damage, clinical doses of these drugs will be used to evaluate if they help prevent observed lesions or enhance their regression.

对于特定的血流动力学应力，待检验的假设为（i） 大脑动脉分叉处的损伤比邻近的 分支或颅外分叉处，以及（ii）此类损伤开始于 从内膜上。 大脑动脉分叉的结构将在 主动脉缩窄高血压、动脉粥样硬化或颈动脉粥样硬化家兔 结扎和人类尸检。 重点是年轻的成年男性 兔子与适当的控制。 定量体视学方法将 为了评论内皮细胞、平滑肌细胞 (SM)内弹性膜（IEL）可能存在机械性无力 导致动脉粥样硬化和动脉瘤形成。 具体目标涉及动脉分叉的结构， 内侧间隙是（a）确定的模式和精确的方向 内皮细胞和SM细胞（B）绘制出分布、位置和大小 IEL中的开窗率（c）定量比例 与非分支段相比，分叉壁的组成（d） 确定蜂窝之间的布置和相互关系， 内膜的非细胞成分。 这些结构参数将 根据（I）位置（II）压力或流量以及（III） 存在相关病理（动脉粥样硬化或动脉瘤）。 人类大脑循环中膜缺陷的发生率非常高， 微小动脉瘤和囊状动脉瘤可能破裂， 蛛网膜下腔出血和动脉痉挛 据认为， 先天性和/或后天性因素可能导致动脉瘤形成 和破裂，但至今没有公认的病因。 Stehbens（1）指出 “关于退行性变化和血液动力学的进一步信息 动脉分叉处的应力是更详细轮廓的先决条件 脑动脉瘤的发病机制”。 只有定量的 机械分析体视学方法可以提供这一点 信息. 实验研究的启示将得到加强，因为 兔脑血管的形态与人脑血管非常相似。 考虑到蛛网膜下腔出血的发生率、死亡率和发病率， 出血，重要的是要回答有关初始 分叉结构的变化可能是 可能导致风险重新评估的脑动脉瘤发病机制 因素 超过一半的美国人死于心血管疾病， 与动脉粥样硬化过程有关， 由于家族性高胆固醇血症，不到5%的病例（2）。 胆固醇喂养的家兔将提供脂肪沉积的数据， 颈动脉大脑和耳分叉 但血压改变， 流动可以提供对多因素和协同作用的见解 导致在侧角形成内膜垫的改变， 关于bifurcation的其他文章 同样的因素导致异常 脑小血管的通透性可能是内膜变化的一个因素 更大的分叉。 此外，由于钙进入阻滞剂可能具有保护作用， 针对内皮和SM损伤，这些药物的临床剂量将 用于评估它们是否有助于预防观察到的病变或增强其 回归分析