Mechanical Regulation of Vascular Growth and Remodeling

 描述(由申请人提供)：组织血管化是自然或辅助再生反应中最关键的组成部分之一。通常，这样的再生区域的特征是新生血管结构穿过正常组织的界面移动到可能具有不同机械性能的愈合区域。虽然这种血管生成过程的分子和细胞性质已经被很好地研究了，但关于影响血管形成的机械力却知之甚少。已经证实，尤其是在肌肉骨骼系统中，有效和早期的血管形成反应是功能再生的核心，其延迟或中断可能对再生过程有害。我们早期的研究表明，机械负荷的时机在修复骨组织及其血管方面同样重要。由此可见，机械环境微妙地调节着血管网络。在拉伸载荷和管腔流体剪切研究中检查的3D结构形成了我们关于微血管与其微环境相互作用的大部分知识基础。在体内，特别是在肌肉骨骼组织中，压缩和剪切--包括块状和界面--是主要的加载方式。我们认为，外部机械载荷将通过直接压缩载荷以及机械载荷和非载荷组织交界处的剪切影响微血管的生长和重塑。这项建议首先在体外模型中研究这些问题，这是体内负荷情景的简单概括。这些研究将为微血管生长和矿化的活体加载模型提供信息，在该模型中，除了外力外，矿化诱导的局部硬度变化可能起到作用。同时，在硅胶研究中，基于已经建立的微血管生长模型的计算框架，将进行修改，以反映当前方法的需要。经过验证的计算模型将允许更详细地检查这些与血管生长和重塑的机械相互作用，更重要的是，基于这种关系建立一个预测框架，最终可能指导创伤后康复计划，甚至是工程化血管支架的设计。

 DESCRIPTION (provided by applicant): Tissue vascularization is one of the most critical components of the natural or assisted regenerative response. Typically, such areas of regeneration are characterized by the presence of nascent vascular structures moving across an interface of normal tissue to healing areas of likely different mechanical properties. Though the molecular and cellular nature of such angiogenic processes are well investigated, not much is known about the mechanical forces that influence the vasculature. It is well established, especially in the musculoskeletal system, that an effective and early vascularization response is central to functional regeneration, a delay or disruption of which can be deleterious to the regenerative process. Our early studies have shown that timing of the mechanical loading is equally important in healing bone tissue and its vascularity. It is thus clear that the mechanical environment exquisitely regulates the vascular networks. 3D constructs examined in tensile loading and luminal fluid shear studies form the bulk of our knowledge base on the interactions of microvessels with their microenvironment. In vivo, especially in musculoskeletal tissue, compression and shear - both bulk and interfacial - are the predominant modes of loading. We believe that external mechanical loading will influence the growth and remodeling of microvasculature by virtue of the direct compressive loads as well as by shear at the interface of the mechanically loaded and unloaded tissue. This proposal examines these questions first in an in vitro model, which is a simplistic recapitulation of the in vivo loading scenario. These studies will inform an in vivo loading model of microvascular growth and mineralization where in addition to the external forces, mineralization induced change in local stiffness is likely to playa role. In parallel, in silico studies, based on an already well-established computational framework for modeling microvascular growth, will be modified to reflect the needs of the current approach. The validated computational model will then allow examination of these mechanical interactions with vascular growth and remodeling in greater detail and more importantly establish a predictive framework based on this relationship that may ultimately guide post-traumatic rehabilitation programs or even the design of engineered vascularized scaffolds.