Regulation of angiogenesis by matrix stiffness in an ECM-mimetic hydrogel

ECM 模拟水凝胶中基质硬度对血管生成的调节

• 批准号: 8145333
• 负责人: Jordan S. Miller
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-13 至 2012-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145333
• 关键词: Adhesions; Adhesiveness; Adhesives; Anastomosis - action; Binding; Blood Vessels; Characteristics; Chemicals; Cleaved cell; Collagen; Communication; Complex; Cues; Development; Diabetes Mellitus; Disease; Endothelial Cells; Event; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Family; Gel; Gelatinase A; Gene Expression; Goals; Human Pathology; Hydrogels; Inhibition of Matrix Metalloproteinases Pathway; Investigation; Legal patent; Malignant Neoplasms; Matrix Metalloproteinases; Mechanics; Mediating; Mediation; Membrane; Modeling; Modification; Peptide Hydrolases; Phenotype; Predisposition; Process; Regulation; Role; Signal Transduction; Specificity; Stimulus; System; Testing; Therapeutic; Tissue Engineering; Tissues; Vertebral column; Work; Wound Healing; angiogenesis; design; extracellular; human MMP14 protein; human disease; in vitro Model; member; mimetics; response; tumor progression

DESCRIPTION (provided by applicant): Angiogenesis, in which endothelial cells (ECs) form new blood vessels from pre-existing ones, is a central component of tissue development, wound healing, and cancer progression. ECs engaged in angiogenesis must negotiate and integrate a complex array of extracellular stimuli: adhesive signals, soluble factors, and mechanical stiffness are known or implicated to have critical roles. ECs integrate extracellular stimuli in concert, so it has been difficult to decouple the contributions of characteristics such as stiffness from other pericellular effectors. What is needed is an experimental system that can be used to independently vary ECM components to allow for the investigation of fundamental EC-mediated angiogenic processes. In this work, we develop and apply a synthetic hydrogel system that can be used to separate and assess the contribution of each of these factors independently. We first examine the effect of stiffness on ex vivo and in vitro models of angiogenesis and the angiogenic phenotype while holding adhesivity constant We have found that angiogenesis exhibits cl biphasic response to stiffness, with gels that are too stiff or too soft unable to support angiogenesis. We next test the hypothesis that stiffness is potentiating the expression of proteolytic enzymes from the matrix metalloproteinase (MMP) family. Finally, we further test our model by holding both adhesivity and stiffness constant and instead varying the MMP-susceptibility of our hydrogel. We will use MMP-inhibition studies to implicate the specific MMPs involved in these remodeling processes. Angiogenesis is a natural process by which new blood vessels form from preexisting ones in growing tissues. However, this natural process is also known to have aberrant effects in human diseases such as cancer and diabetes. The goal of this project is to, at a fundamental level, understand the cellular events and chemical communication involved in this process which will ultimately allow the development of new disease therapies.

描述（由申请人提供）：血管生成，即内皮细胞（EC）从预先存在的血管形成新血管，是组织发育、伤口愈合和癌症进展的核心组成部分。参与血管生成的内皮细胞必须协调和整合一系列复杂的细胞外刺激：已知或暗示粘附信号、可溶性因子和机械刚度具有关键作用。 EC 协调一致地整合细胞外刺激，因此很难将硬度等特性的贡献与其他细胞周效应器分开。我们需要的是一个可用于独立改变 ECM 成分的实验系统，以便研究基本的 EC 介导的血管生成过程。在这项工作中，我们开发并应用了一种合成水凝胶系统，该系统可用于独立分离和评估每个因素的贡献。我们首先检查硬度对离体和体外血管生成模型和血管生成表型的影响，同时保持粘附性恒定。我们发现血管生成对硬度表现出 cl 双相反应，太硬或太软的凝胶都无法支持血管生成。接下来，我们测试了以下假设：硬度会增强基质金属蛋白酶 (MMP) 家族中蛋白水解酶的表达。最后，我们通过保持粘附性和刚度恒定并改变水凝胶的 MMP 敏感性来进一步测试我们的模型。我们将使用 MMP 抑制研究来揭示参与这些重塑过程的特定 MMP。血管生成是生长组织中现有血管形成新血管的自然过程。然而，这种自然过程也对癌症和糖尿病等人类疾病产生异常影响。该项目的目标是从根本上了解该过程中涉及的细胞事件和化学通讯，这最终将有助于开发新的疾病疗法。