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: 10247363
• 负责人: Ryan S. Udan
• 金额: $ 1.05万
• 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/10247363
• 关键词: Adhesions; Adhesiveness; Adhesives; Adult; Architecture; Attenuated; Biomedical Research; Blood Vessels; Blood flow; Caliber; Cell-Matrix Junction; Complex; Defect; Disease; Embryo; Engineering; Enzymes; Exhibits; Exposure to; Extracellular Matrix; Future; Genes; Goals; Growth; Heart; Investments; Matrix Metalloproteinase Inhibitor; Medical; Modeling; Molecular; Mus; Nutrient; Organ; Oxygen; Principal Investigator; Process; Proteins; Research; Research Personnel; SEMA3F gene; Scientist; Semaphorin-3A; Signaling Protein; Smooth Muscle Myocytes; Students; Testing; Thick; Thinness; Tissue Engineering; Training Support; Vascular Smooth Muscle; base; blood damage; blood vessel development; hemodynamics; inhibitor/antagonist; organ growth; organ injury; recruit; repaired; 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 larger- 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.

项目概要 未来医疗的一个重要步骤将是用器官替代患病或受伤的器官。 在体外生长的工程器官。然而，实现这一目标的一个主要障碍是 组织工程师培育出复杂且有功能的血管，为这些血管提供氧气和营养 体外生长的器官。谜题中缺少的一个部分是了解血液厚度的差异如何 血管壁在整个脉管系统中形成。出于这个原因，研究人员必须了解更大的- 直径血管（靠近心脏）形成由血管层组成的厚血管壁 平滑肌细胞 (vSMC)，以及小直径血管（远离心脏）如何形成薄或 vSMC 层缺失。容器壁厚的这些差异是形成的关键要求 功能性脉管系统的结构，但尚不清楚壁厚是如何调节的。因此，长期目标 该提案旨在阐明控制血管壁厚度形成的机制。来自我们的 之前的研究中，我们确定发育中的血管会根据血管壁的程度形成厚血管壁。 暴露于血流力。因此，高流量血管比低流量血管募集并附着更多的 vSMC 船只。目前尚不清楚的是解释血流力量如何产生的具体机制 （血流动力学力）调节 vSMC 募集和附着。研究小组利用小鼠胚胎模型 本科生、硕士生和首席研究员将探索两大机制 关于如何获得血管壁厚度。在目标1中，我们将测试血流动力是否 调节多种 Semaphorin3 信号蛋白（Sema3F/G 和 Sema3A）的表达以控制 vSMC 招募到高流量血管。将通过破坏这些 Sema3 蛋白来研究这一目标，以确定 如果这阻碍了 vSMC 募集至脉管系统，并通过挽救所表现出的 vSMC 募集缺陷 当血流量减少时，通过重新引入 Sema3 蛋白梯度。在目标 2 中，我们将测试是否 血流动力调节血管的粘附性，促进 vSMC 附着于血管。这个目标 将通过确定血流量的减少是否会降低 vSMC 附着的能力来进行研究 通过减弱粘附分子的表达来抑制血管，例如细胞外基质基因（或抑制剂） 细胞外基质降解酶），并通过上调细胞外基质降解酶的表达 基因（基质金属蛋白酶 [Mmp] 抑制剂）。为此，我们还将确定是否使用 Mmp 抑制剂 将增强细胞外基质的形成，从而增强血管与 vSMC 的粘附。由 确定 vSMC 的血管壁投资机制，这将使研究人员能够确定 一套适当的分子工具，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生和 从事生物医学研究的硕士生。