Measuring the effect of extracellular mechanics on smooth muscle contractility

测量细胞外力学对平滑肌收缩力的影响

基本信息

批准号：
8689013
负责人：
PATRICK W ALFORD
金额：
$ 6.55万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Arteries exist in a dynamic environment, necessitating constant adaptation by vascular smooth muscle cells (VSMCs), in order to maintain mechanical homeostasis. In a healthy artery, maintenance of vessel tension is primarily achieved by contraction and relaxation of VSMCs, and loss of contractility is indicative of VSMC dysfunction, which may play an important role in pathogenesis of atherosclerotic plaque formation and restenosis. The mechanical environment can be significantly perturbed by plaque development or stent implantation, either by softening of the tissue, due to lipid pools in atherosclerosis, or stiffening due to calcified regions of the plaque, or an implanted stent. Recent results have found that the mechanics of a cell's surroundings play a significant role in its functional behavior, suggesting that non-homeostatic tissue mechanics, due to plaques or stents, could also affect contractile function. We hypothesize that the mechanics of the surrounding tissue directly affects vascular smooth muscle cells' contractile functionality. With current techniques, it is difficult to assess the effects of tissue stiffness on VSMC function because existing in vitro systems in which mechanics are independently controllable are all limited to narrow ranges of substrate stiffness over which they can be used to measure cell or tissue stress generation. So, to test this hypothesis we will need to develop a new method for measuring tissue stress that can be employed with a wide range of substrate mechanics. We have previously developed a method called vascular muscular thin films (vMTFs), where we micropatterned cells into highly organized tissues on a thin rubber beam, and the cell stress was determined by measuring the curvature of the beam. We will adapt this method to include a variable modulus substrate, allowing us to measuring functional contractility of VSMCs mimicking a wide range of mechanical environments, such as soft lipid pools and stiff stents. We will then correlate this contractility with VSMC phenotype marker expression to determine how phenotype switching, which has been implicated in a number of VSMC dysfunctions, plays a role in VSMC substrate-modulated mechano-adaptation. Completion of this work will provide a sharper picture of the functional implications of the evolving mechanical environment of VSMCs in arterial pathologies.

描述（由申请人提供）：动脉存在于动态环境中，需要通过血管平滑肌细胞（VSMC）持续适应，以维持机械稳态。在健康的动脉中，血管张力的维持主要是通过收缩和VSMC的放松来实现的，而收缩力的丧失表明VSMC功能障碍可能在动脉粥样硬化斑块形成和再肾上腺炎的发病机理中起重要作用。机械环境可以通过牙菌斑的发育或支架植入来显着干扰组织，要么是由于动脉粥样硬化中的脂质池而导致的组织软化，要么是由于牙菌斑的钙化区域或植入支架而导致的。最近的结果发现，细胞周围环境的力学在其功能行为中起着重要作用，表明由于斑块或支架而导致的非固定组织力学也可能影响收缩功能。我们假设周围组织的力学直接影响血管平滑肌细胞的收缩功能。借助当前技术，很难评估组织刚度对VSMC功能的影响，因为现有的体外系统可独立控制的体外系统都限于狭窄的底物刚度范围，可用于测量细胞或组织应激的产生。因此，为了检验这一假设，我们将需要开发一种新方法来测量可以用广泛的底物力学使用的组织应力。我们以前已经开发了一种称为血管肌肉薄膜（VMTF）的方法，在该方法中，我们将微图案的细胞在薄橡胶束上的高度有组织的组织中，并通过测量束的曲率来确定细胞应力。我们将适应此方法以包含一个可变模量底物，从而使我们能够测量模仿各种机械环境的VSMC的功能收缩率，例如软脂质池和硬固定支架。然后，我们将将这种收缩性与VSMC表型标记物表达相关联，以确定表型切换与许多VSMC功能障碍有关的转换如何在VSMC底物修饰的机械改装中起作用。这项工作的完成将为动脉病理中VSMC不断发展的机械环境的功能含义提供更清晰的图片。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Empirically Determined Vascular Smooth Muscle Cell Mechano-Adaptation Law.

DOI：
10.1115/1.4036454
发表时间：
2017-07
期刊：
Journal of biomechanical engineering
影响因子：
0
作者：
Kerianne E. Steucke;Zaw Win;Taylor R. Stemler;Emily E. Walsh;Jennifer L. Hall;Patrick W. Alford
通讯作者：
Kerianne E. Steucke;Zaw Win;Taylor R. Stemler;Emily E. Walsh;Jennifer L. Hall;Patrick W. Alford

Vascular smooth muscle cell functional contractility depends on extracellular mechanical properties.