Blood flow and structural adaptation in microcirculation

微循环中的血流与结构适应 项目总结 血管生成(新血管的生长)是一系列生理和病理过程的中心。 包括发育、生长、运动、发情周期、伤口愈合、侧枝形成等过程 缺血、新生血管性黄斑变性和肿瘤生长。许多关于血管生成的研究都集中在 关于血管形成的细胞和分子过程。具有足够功能属性的网络如何 都是通过血管生成、适应(重塑)和修剪(移除)血管形成的，已经收到 更少的关注。这个项目使用理论模型来解决以下问题：过程是如何 血管生成、结构适应和修剪产生的血管结构符合 组织的功能需求？新生小鼠发育中的视网膜被广泛用作 研究血管生成的动物模型。出生后，视网膜微循环通过发芽迅速传播 血管生成，在出生后第9天形成覆盖在视网膜内表面的初级神经丛。在.期间 从P8到P14，来自这个网络的芽潜入视网膜，在视网膜内的两个不同层面形成新的网络 视网膜。来自这个特性良好的实验系统的大量数据的可用性提供了 为开发详细的理论模型以及使用这些模型来确定 功能网络结构形成的特定生物学机制。具体目标1是开发 初级视网膜神经丛在P1-P9期间生长的二维模型。基于细分市场的 将使用方法来描述网络结构、增长、适应和修剪以及连续场 氧气和生长因子扩散的模型将被使用。以下生物机制将是 包括：在缺氧区产生生长因子；通过生长刺激萌芽的血管生成 因素；侧向抑制顶端细胞形成以控制芽体密度；内皮顶端引导芽体生长 细胞.用已有的星形胶质细胞网络引导萌芽.血管直径的结构适应 对壁面剪切力、压力、代谢条件和传导反应的反应；以及修剪 多余的船只。需要解决的问题是：它们各自的作用和重要性是什么 生物机制？它的调整或取消会产生什么影响？将对模型预测进行比较 对野生型和转基因动物进行了观察。具体目标2是开发三个- 深部神经丛生长和初级神经丛退缩的量纲模型 在P8-P14期间。建模方法将扩展到三维。氧气变化的影响 通过视网膜的生长因子水平将被包括在内。这些研究将为我们提供对 新生儿功能性血管网络形成速度惊人的机制 小鼠视网膜，为控制血管结构的实验工作提供了新的方向，并形成了 为治疗目的开发干预措施以控制血管生成的合理依据。

BLOOD FLOW AND STRUCTURAL ADAPTATION IN MICROCIRCULATION PROJECT SUMMARY Angiogenesis (growth of new blood vessels) is central to a wide range of physiological and pathological processes, including development, growth, exercise, estrus cycle, wound healing, collateral formation following ischemia, neovascular macular degeneration, and tumor growth. Much research on angiogenesis has focused on the cellular and molecular processes of vessel formation. How networks with adequate functional properties are formed, through angiogenesis, adaptation (remodeling) and pruning (removal) of vessels, has received less attention. This project uses theoretical models to address the following question: How do the processes of angiogenesis, structural adaptation and pruning generate vascular structures that meet the functional needs of the tissue? The developing retina of the neonatal mouse is used extensively as an animal model for studying angiogenesis. After birth, the retinal microcirculation spreads rapidly by sprouting angiogenesis to form a primary plexus covering the inner surface of the retina by P9 (postnatal day 9). During P8 to P14, sprouts from this network dive into the retina, forming new networks at two different levels within the retina. The availability of a large amount of data from this well-characterized experimental system provides a strong basis for developing detailed theoretical models, and for using these models to determine the roles of specific biological mechanisms in the formation of functional network structures. Specific Aim 1 is to develop two-dimensional models for the growth of the primary retinal plexus during P1-P9. A segment-based approach will be used to describe network structure, growth, adaptation and pruning, and continuous field models will be used for oxygen and growth factor diffusion. The following biological mechanisms will be included: production of growth factors in hypoxic regions; stimulation of sprouting angiogenesis by growth factors; lateral inhibition of tip cell formation to control sprout density; growth of sprouts led by endothelial tip cells; guidance of sprouts by the preexisting network of astrocytes; structural adaptation of vessel diameters in response to wall shear stress, pressure, metabolic conditions and conducted responses; and pruning of redundant vessels. The questions to be addressed are: What is the role and importance of each of these biological mechanisms? What are the effects of its modulation or abolition? Model predictions will be compared with observations in wild-type and genetically modified animals. Specific Aim 2 is to develop three- dimensional models for the growth of the deeper plexuses and the regression of the primary plexus during P8-P14. The modeling approach will be extended to three dimensions. Effects of variations in oxygen and growth factor levels through the retina will be included. These studies will provide insight into the mechanisms by which functional vascular networks are generated with remarkable speed in the neonatal mouse retina, suggest new directions for experimental work on control of vascular structure, and form a rational basis for developing interventions to control angiogenesis for therapeutic purposes.