Hemodynamic Forces in Vascular Remodeling

描述(由申请人提供)： 在这项建议中，我们提出的假设是，血流动力学力量，如壁面剪应力，是正常的血管形成和小鼠胚胎发育重塑的中心。剪切力发挥重要作用的建议已经被多次提出，这一理论得到了一些支持；然而，很少有定量实验在完整的胚胎中对其进行体内测试。为此，建议的工作将开发基于图像的形态重塑的定量指标，允许与活体测量的血流动力学特性进行统计比较。 该提案需要非侵入性成像技术的技术开发，特别是磁共振显微镜(MRM)成像。MRM将用于测量血浆速度、血容量和整个胚胎的局部血流，仅使用内源性图像对比度。激光共聚焦扫描显微镜(CLSM)将解决直接飞行时间测量的红细胞流动和内皮运动在更有限的区域形成的胚胎血管。使用两种成像方式可以进行互补的血流定量和交叉验证。 血流、脉动度和红细胞压积的实验扰动会导致发育中的血管系统的血液动力发生变化。MRM和CLSM都将表征微扰；血流动力的变化将与形态重塑指数相关。总体而言，这些方法将定义在正常发育和血液流动中断时发生的形态动态变化。形态变化将与揭示流动和发展如何相互联系的定量数据相关。这些实验将建立一个模型系统来研究液体对血管形成的影响。一旦建立了这个模型，就可以开始研究机械感觉信号和遗传信号通路之间的相互作用。 (摘要结束)

DESCRIPTION (provided by applicant): In this proposal we address the hypothesis that hemodynamic forces, such as wall shear-stress, are central to normal vascular formation and remodeling in mouse embryonic development. The proposal that shear stress plays an important role has been made many different times and there has been some support for this theory; however, few quantitative experiments have tested it in vivo in an intact embryo. To this end, the proposed work will develop image-based quantitative indices of morphological remodeling which allow statistical comparison with measured hemodynamic properties in vivo. The proposal requires technical development of the non-invasive imaging techniques, particularly magnetic resonance microscopy (MRM) imaging. MRM will be used to measure blood plasma velocity, blood volume and regional flow across the whole embryo using endogenous image contrast alone. Confocal laser scanning microscopy (CLSM) will address direct time-of-flight measurements of erythrocyte flow and endothelial motion over more limited regions of the forming embryonic vasculature. Use of two imaging modalities allows complementary flow quantitation and cross-validation. Experimental perturbations of flow, pulsatility and hematocrit result in changes in hemodynamic forces on the developing vasculature. Perturbations will be characterized with both MRM and CLSM; the changes in hemodynamic forces will be correlated with morphological remodeling indices. Overall, these approaches will define the dynamic changes in morphology that occur in normal development and when blood flow is disrupted. Morphological changes will be related to quantitative data revealing how flow and development are interlinked. These experiments will establish a model system to study fluid effects on vascularization. Once this model has been established, studies to understand the interplay between mechano-sensory signals and genetic signaling pathways can begin. (End of Abstract)