Role of endothelial Sox17 in EC-SMC crosstalk and homeostatic regulation of blood vessel adaption to arterial hemodynamics

内皮 Sox17 在 EC-SMC 串扰和血管适应动脉血流动力学的稳态调节中的作用

基本信息

批准号：
10419063
负责人：
Guohao Dai
金额：
$ 58.94万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10419063
关键词：
Address Adult Anatomy Aneurysm Animal Model Arteries Biomechanics Biomedical Engineering Blood Vessels Caliber Cell Proliferation Coculture Techniques Connexins Data Development Developmental Biology Disease Elastin Endothelial Cells Endothelium Environment Ephrins Exhibits Extracellular Matrix Family Fistula Gene Expression Profile Genes Genetic Transcription Human Hyperplasia Impairment In Vitro Knowledge Life MYH11 gene Mediating Modeling Molecular Molecular Profiling Molecular Target Mus Pathologic Pathway interactions Periodicity Phenotype Physiology Platelet-Derived Growth Factor Platelet-Derived Growth Factor beta Receptor Play Process Production Property Regulation Role SOX13 gene SOX17 gene Semaphorins Series Signal Transduction Smooth Muscle Myocytes Stenosis Structure System Testing Tetanus Helper Peptide Therapeutic Intervention Thick Tissue Engineering Translating Vascular Diseases Vascular Graft Vascular remodeling Vein graft Veins Venous arterial remodeling base calponin clinical application decorin design differential expression hemodynamics improved in vivo insight mechanotransduction mouse model notch protein programs public health relevance reconstitution recruit response transcription factor vascular tissue engineering

项目摘要

SUMMARY Arteries and veins play different roles in human physiology and vascular diseases. Notably, arterial and venous endothelial cells (ECs) demonstrate distinct molecular profiles. The establishment of such molecular distinction is orchestrated by series of transcriptional programs, which have been well studied in developmental biology. However, how these EC transcriptional programs control adult blood vessel structure and function, and how to translate this knowledge into clinical application such as vein or tissue engineered graft adaptation is under- explored. To address this question, we examined the transcription profile of arterial vs. venous ECs in adult blood vessels and have identified several key transcription factors that are differentially expressed in arterial vs. venous ECs. Among them, Sox13 and Sox17 are highly expressed in adult arterial ECs but not in venous ECs. Our preliminary studies demonstrate that over-expressing Sox17 in venous ECs reconstitutes all the known arterial markers, suggesting Sox17 is a key regulator of adult arterial EC phenotypes. Importantly, Sox17 induces the expression of multiple families of molecules (Notch, Ephrin, Connexins, PDGF) that may confer signals from ECs to smooth muscle cells (SMCs) to regulate SMC phenotypes in blood vessels. EC Sox17 also promoted SMC contractile phenotype in EC-SMC co-culture and graft remodeling model. On the other hand, over-expressing Sox13 in ECs facilitates the recruitment of SMCs toward blood vessels. Based on these encouraging preliminary data, we hypothesize that endothelial Sox13/17 play synergistic roles in the homeostatic regulation of adult artery functions by maintaining adult arterial EC phenotype and engaging EC- SMC crosstalk. To test this hypothesis, we will investigate how the endothelial Sox13/17 regulates EC and SMC phenotypes and their role in blood vessel structures and functions using in vitro bioengineered models as well as in vivo animal models.

概括动脉和静脉在人类生理和血管疾病中起不同的作用。值得注意的是，动脉和静脉内皮细胞（EC）表现出不同的分子谱。建立这种分子区别由一系列转录程序精心策划，这些程序在发育生物学方面进行了很好的研究。但是，这些EC转录程序如何控制成人血管结构和功能，以及如何将这些知识转化为临床应用，例如静脉或组织工程移植的适应探索。为了解决这个问题，我们检查了成人动脉和静脉EC的转录谱血管并鉴定了几种在动脉中差异表达的关键转录因子 vs.静脉EC。其中，Sox13和Sox17在成年动脉EC中高度表达，但不在静脉 ECS。我们的初步研究表明，静脉EC中过度表达的Sox17重构了所有已知的动脉标记，表明SOX17是成年动脉EC表型的关键调节剂。重要的是， Sox17诱导了多个分子家族（Notch，Ephrin，connexins，pDGF）的表达将信号从EC授予平滑肌细胞（SMC），以调节血管中的SMC表型。 EC SOX17还促进了EC-SMC共培养和移植重塑模型中的SMC收缩表型。在另一方面，ECS中过表达的Sox13有助于将SMC募集到血管上。基于这些令人鼓舞的初步数据，我们假设内皮Sox13/17在通过维持成年动脉EC表型并吸引EC-来调节成人动脉功能 SMC串扰。为了检验这一假设，我们将研究内皮SOX13/17如何调节EC和 SMC表型及其在血管结构和功能中的作用，并使用体外生物工程模型作为以及体内动物模型。