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的最关键组成部分之一。通常，这种再生区域的特征在于存在新生血管结构，其穿过正常组织的界面移动到可能具有不同机械特性的愈合区域。虽然这种血管生成过程的分子和细胞性质得到了很好的研究，但对影响脉管系统的机械力知之甚少。已经充分确定，特别是在肌肉骨骼系统中，有效和早期的血管化反应是功能性再生的核心，其延迟或中断可能对再生过程有害。我们早期的研究表明，机械负荷的时机在愈合骨组织和其血管分布方面同样重要。因此，很明显，机械环境精细地调节血管网络。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-体积和界面-是主要的加载模式。我们认为，外部机械负荷将影响微血管的生长和重塑的直接压缩负荷，以及通过剪切在界面处的机械加载和卸载组织。该建议首先在体外模型中检查这些问题，该模型是体内加载情况的简单概括。这些研究将为微血管生长和矿化的体内负荷模型提供信息，其中除了外力外，矿化诱导的局部刚度变化可能起作用。与此同时，基于已经建立的微血管生长建模计算框架的计算机模拟研究将进行修改，以反映当前方法的需求。然后，经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，最终可以指导创伤后康复计划，甚至设计工程化血管化支架。

 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.