Mechanisms of hemodynamic-force-regulated vascular smooth muscle cell recruitment and attachment

血流动力学力调节血管平滑肌细胞募集和附着的机制

• 批准号: 10046374
• 负责人: Ryan S. Udan
• 金额: $ 41.57万
• 依托单位: MISSOURI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046374
• 关键词: 3-Dimensional; Academic Research Enhancement Awards; Adhesions; Adhesiveness; Adhesives; Adult; Architecture; Attenuated; Automobile Driving; Basement membrane; Biomedical Research; Blood Vessels; Blood flow; Caliber; Cell Adhesion; Cell-Matrix Junction; Chemotactic Factors; Complex; Defect; Deposition; Development; Developmental Biology; Diffuse; Disease; Distal; Embryo; Endothelium; Engineering; Enzymes; Exhibits; Exposure to; Extracellular Matrix; Future; Genes; Goals; Growth; Heart; Impairment; Injections; Institution; Investments; Literature; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Medical; Mesoderm; Modeling; Molecular; Mus; Nutrient; Organ; Oxygen; Principal Investigator; Process; Proteins; Regenerative Medicine; Research; Research Personnel; Role; SEMA3F gene; Scientist; Semaphorin-3A; Semaphorins; Signaling Protein; Site; Smooth Muscle Myocytes; Students; Testing; Thick; Thinness; Tissue Engineering; Tissues; Training Support; Trees; Tunica Media; Vascular Smooth Muscle; Yolk Sac; base; blood damage; blood vessel development; hemodynamics; in vivo; inhibitor/antagonist; organ growth; organ injury; recruit; repaired; success; tool; undergraduate student

Project summary In the future, an important step in medical treatment will be the replacement of diseased or injured organs with engineered organs grown outside the body. However, one major impediment towards this goal is the ability for tissue engineers to grow complex and functional blood vessels that supply oxygen and nutrients to these externally grown organs. A missing piece of the puzzle is in knowing how differences in thickness of the blood vessel wall forms throughout the vasculature. For this reason, researchers must understand how large- diameter blood vessels (located close to the heart) form thick vessel walls composed of layers of vascular smooth muscle cells (vSMCs), and how small-diameter vessels (located far away from the heart) form thin or absent layers of vSMCs. These differences in vessel wall thickness are critical requirements for the formation of a functional vasculature, but it is unclear how wall thickness is regulated. Thus, the long-term objective of this proposal is to elucidate the mechanisms governing the formation of blood vessel wall thickness. From our previous studies, we determined that developing blood vessels form thick vessel walls based on extent of exposure to blood flow forces. Thus, high-flow vessels recruit and attach to more vSMCs than low-flow vessels. What remains unknown are the specific mechanisms explaining how the force of blood flow (hemodynamic force) regulates vSMC recruitment and attachment. Using the mouse embryonic model, a team of undergraduate students, master’s students and the principal investigator will explore two major mechanisms regarding how vessel wall thickness is attained. In aim 1, we will test the whether hemodynamic force regulates expression of several Semaphorin3 signaling proteins (Sema3F/G and Sema3A) to control vSMC recruitment to high-flow vessels. This aim will be investigated by disrupting these Sema3 proteins to determine if this impedes vSMC recruitment to the vasculature, and by rescuing the vSMC recruitment defects exhibited upon reduction of blood flow, by reintroducing the Sema3 protein gradients. In aim 2, we will test whether hemodynamic force regulates the adhesiveness of vessels to promote vSMC attachment to vessels. This aim will be investigated by determining whether reduction of blood flow reduces the ability for vSMCs to attach to vessels by attenuating expression of adhesive molecules, such as extracellular matrix genes (or inhibitors to extracellular matrix-degrading enzymes), and by upregulating expression of extracellular matrix-degrading genes (Matrix metalloproteinase [Mmp] inhibitors). In this aim, we will also determine if use of Mmp inhibitors will enhance extracellular matrix formation, and as a result enhance the adhesion of vessels to vSMCs. By the determining the mechanisms of vessel wall investment with vSMCs, this will allow researchers to identify an appropriate set of molecular tools that will be used to engineer functional blood vessels, as well as repair damaged blood vessels in adults. Further, these studies will help support the training of undergraduate and master’s students in biomedical research.

项目摘要 将来，医疗方面的重要一步将是用 设计的器官在体外生长。但是，对此目标的一个主要障碍是 组织工程师生长复杂且功能性的血管，这些血管向这些供应氧气和养分 外部生长器官。缺少的难题是知道血液厚度的差异 整个脉管系统形成容器壁。因此，研究人员必须了解 直径血管（位于心脏附近）形成由血管层组成的厚容器壁 平滑肌细胞（VSMC），以及直径的小血管（远离心脏）的形成薄或 不存在VSMC的层。船只壁厚的这些差异是形成的关键要求 功能性脉管系统，但尚不清楚如何调节壁厚。那是长期目标 该建议是阐明管理血管壁厚厚度形成的机制。来自我们的 先前的研究，我们确定发育血管根据范围形成厚血管壁 暴露于血流。那是高流量的招募和附着比低流量更多的VSMC 船只。尚不清楚的是特定机制解释了血流的力量 （血流动力）调节VSMC募集和依恋。使用鼠标胚胎模型，团队 本科生，硕士学生和主要研究人员将探索两个主要机制 考虑如何连接容器壁厚。在AIM 1中，我们将测试血液动力学是否 调节几种Semaphorin3信号蛋白（SEMA3F/G和SEMA3A）的表达以控制VSMC 招募高流量视频。将通过破坏这些SEMA3蛋白来确定该目标 如果这阻碍了VSMC招募到脉管系统，并通过营救VSMC招募缺陷暴露 血流减少后，通过重新引入SEMA3蛋白梯度。在AIM 2中，我们将测试是否 血液动力学调节血管的粘附性以促进VSMC附着在血管上。这个目标 通过确定减少血流是否会降低VSMC附着在 通过衰减粘合分子的表达，例如细胞外基质基因（或抑制剂对 细胞外基质酶），并通过上调细胞外基质降解的表达 基因（基质金属蛋白酶[MMP]抑制剂）。在此目标中，我们还将确定是否使用MMP抑制剂 将增强细胞外基质形成，因此增强了血管对VSMC的粘合剂。由 通过VSMC确定船只墙投资的机制，这将使研究人员能够确定 适当的分子工具将用于设计功能性血管以及修复 成人血管受损。此外，这些研究将有助于支持本科和 硕士生生物医学研究的学生。