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，医疗的一个重要步骤将是用人工心脏替换患病或受伤的器官。 体外培养的工程器官然而，实现这一目标的一个主要障碍是， 组织工程师培养复杂和功能性的血管，为这些组织提供氧气和营养。 外部生长的器官这个谜题的一个缺失部分是，血液厚度的差异 血管壁在整个脉管系统中形成。为此，研究人员必须了解有多大- 直径的血管（位于心脏附近）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（位于远离心脏）如何形成薄或 缺乏vSMC层。血管壁厚度的这些差异是形成血管壁的关键要求。 但目前尚不清楚壁厚是如何调节的。因此， 该建议旨在阐明控制血管壁厚度形成的机制。从我们 以前的研究，我们确定，发展中的血管形成厚的血管壁的基础上的程度， 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。 船舶.目前尚不清楚的是解释血液流动的力量如何 （血流动力学力）调节vSMC募集和附着。利用小鼠胚胎模型， 本科生、硕士生和主要研究者将探索两大机制 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学力是否 调节几种Semaphorin 3信号蛋白（Sema 3F/G和Sema 3A）的表达以控制vSMC 招募到高流量血管。这一目的将通过破坏这些Sema 3蛋白来研究，以确定 如果这阻碍了vSMC募集到血管系统，并通过挽救vSMC募集缺陷表现出的 在血流减少时，通过重新引入Sema 3蛋白梯度。在目标2中，我们将测试 血流动力学力调节血管的扩张，促进vSMC与血管的附着。这一目标 将通过确定血流量减少是否降低vSMC附着于 通过减弱粘附分子的表达，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）在这个目标中，我们还将确定是否使用Mmp抑制剂， 将增强细胞外基质形成，并因此增强血管与vSMC的粘附。由 确定血管壁投资与vSMC的机制，这将使研究人员能够确定一个 一套合适的分子工具，将用于工程功能血管，以及修复 成年人的血管受损此外，这些研究将有助于支持本科生的培训， 生物医学研究的硕士生