Hemodynamic Forces in Vascular Remodeling

描述（由申请人提供）： 在这个建议中，我们解决的假设，血液动力学的力量，如壁剪切应力，是中央正常的血管形成和重塑在小鼠胚胎发育。剪切应力起着重要作用的建议已经提出了许多不同的时间，并有一些支持这一理论;然而，很少有定量实验在体内测试它在一个完整的胚胎。为此，拟议的工作将开发基于图像的定量指标的形态重塑，允许在体内测量的血液动力学特性的统计比较。 该提案要求开发非侵入性成像技术，特别是磁共振显微镜成像。MRM将用于仅使用内源性图像对比度测量整个胚胎的血浆速度、血容量和区域流量。共聚焦激光扫描显微镜（CLSM）将解决直接的飞行时间测量的红细胞流动和内皮细胞的运动在更有限的区域形成胚胎血管。使用两种成像模式允许互补的流量定量和交叉验证。 血流、脉动性和红细胞压积的实验扰动导致发育中的脉管系统上的血液动力学力的变化。扰动将采用MRM和CLSM表征;血流动力学的变化将与形态重塑指数相关。总的来说，这些方法将定义在正常发育和血流中断时发生的形态学动态变化。形态变化将与揭示流动和发展如何相互联系的定量数据有关。这些实验将建立一个模型系统来研究流体对血管化的影响。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。 (End摘要）

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)