Effect of shear stress on coronary smooth muscle maturation

剪切应力对冠状动脉平滑肌成熟的影响

基本信息

  • 批准号:
    10580556
  • 负责人:
  • 金额:
    $ 39.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-15 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Project Summary The broad objective of this proposal is to understand why the developing coronary arteries are consistently formed at specific locations. During development of the coronary arteries, numerous immature coronary strands connect to the aorta and then remodel to form the two mature arteries observed in the adult heart. During this remodeling process, one of the biggest changes applied to the newly connected coronary vasculature is the sudden onset of fluid shear stress, yet the regulatory role of fluid shear stress on the development of the coronary vasculature is completely unknown. This proposal specifically addresses how the onset of blood flow, which causes shear stress, induces signaling pathways that would promote smooth muscle migration, proliferation, and maturation. Aim 1 examines the environment surrounding the aorta during the early stages of smooth muscle recruitment to the coronaries. Low levels of shear stress are predicted to promote expression of ET1 and thus lead to matrix metalloprotease (MMP) activity, yielding an environment that promotes smooth muscle migration. This aim will evaluate ET1, MMP2, and MMP9 expression as well as smooth muscle proliferation in the developing coronary arteries of the chick embryo. In ovo injection of MMP2 and 9 inhibitors will confirm the necessity of these MMPs for smooth muscle migration. Aim 2 examines the effects of increased levels of shear stress on cell signaling, particularly the transcription factor KLF2 and the nitric oxide synthase eNOS. High levels of shear stress are predicted to induce KLF2 and lead to eNOS phosphorylation, which promote smooth muscle maturation. Asymmetrical shear stress would thus selectively mature smooth muscle, explaining the consistent patterning of the coronary arteries. In ovo inhibition of eNOS activity will confirm whether eNOS activity is required for smooth muscle maturation and coronary artery stability. Most of the proposed techniques are easily accessible to undergraduate research students, and the preliminary data were generated by undergraduate students, supporting the feasibility of this project at the University of Portland. Altogether, this proposal sits at the intersection among physical forces, molecular responses, and cellular behavior, with the end objective of understanding the formation of the coronary arteries. By better understanding the normal development of these arteries, the proposed research will support future work to examine how these developmental processes go awry, leading to life-threatening congenital coronary artery anomalies.
项目摘要 这项提议的主要目的是了解为什么发育中的冠状动脉总是 形成于特定的位置。在冠状动脉的发育过程中, 股连接到主动脉,然后重塑,形成两个成熟的动脉在成人心脏观察。 在这个重塑过程中,最大的变化之一适用于新连接的冠状动脉, 血管是流体剪切应力的突然发生,然而流体剪切应力对血管的调节作用是不确定的。 冠状血管的发展是完全未知的。该提案具体涉及如何 血液流动的开始,引起剪切应力,诱导信号通路,促进平滑肌 迁移、增殖和成熟。目的1检查主动脉周围的环境, 冠状动脉平滑肌募集的早期阶段。预计低水平的剪切应力 促进ET 1的表达,从而导致基质金属蛋白酶(MMP)活性,产生环境 促进平滑肌迁移。该目的将评估ET 1、MMP 2和MMP 9的表达, 鸡胚冠状动脉平滑肌增生。MMP2的卵内注射 和9种抑制剂将证实这些MMP对于平滑肌迁移的必要性。目标2审查了 剪切应力水平的增加对细胞信号传导的影响,特别是转录因子KLF2和 一氧化氮合酶预计高水平的剪切应力诱导KLF 2并导致eNOS 磷酸化,促进平滑肌成熟。因此,不对称的剪切应力将选择性地 成熟的平滑肌,解释了冠状动脉的一致模式。eNOS的卵内抑制 活性将证实eNOS活性是否是平滑肌成熟和冠状动脉粥样硬化所必需的。 稳定大多数提出的技术是很容易获得的本科研究生,和 初步数据由本科生生成,支持该项目在 波特兰大学。总而言之,这一提议位于物理力、分子力和分子力之间的交叉点。 反应和细胞行为,最终目的是了解冠状动脉的形成, 动脉通过更好地了解这些动脉的正常发育,拟议的研究将支持 未来的工作,以研究这些发展过程是如何出错,导致危及生命的先天性 冠状动脉异常

项目成果

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