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，其中内皮细胞（ECS）是由既存的血管形成新血管的，是组织发育，伤口愈合和癌症进展的核心组成部分。从事血管生成的EC必须协商并整合复杂的细胞外刺激阵列：已知或暗示具有关键作用的粘合信号，可溶性因子和机械刚度。 ECS在协同中整合了细胞外刺激，因此很难将特征的贡献（例如其他细胞周围效应子的刚度）解脱出来。需要的是一个实验系统，可用于独立改变ECM组件，以允许研究基本的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个合成水凝胶系统，该系统可用于分离和评估每个因素的贡献。我们首先检查了刚性对血管生成和血管生成表型的体外模型的影响，同时保持粘附性常数时，我们发现血管生成表现出对刚度的Cl双相反应，而凝胶太僵硬或太软无法支撑血管生成。接下来，我们检验了一个假说，即刚度增强了来自基质金属蛋白酶（MMP）家族的蛋白水解酶的表达。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抑制研究暗示这些重塑过程中涉及的特定MMP。血管生成是一个自然过程，通过在生长组织中已经存在的新血管形成新的血管。然而，众所周知，这种自然过程对癌症和糖尿病等人类疾病具有异常影响。该项目的目的是在基本层面上了解此过程中涉及的细胞事件和化学交流，最终将允许开发新的疾病疗法。