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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：
10630119
负责人：
Guohao Dai
金额：
$ 58.02万
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/10630119
关键词：
Address Adult Anatomy Aneurysm Animal Model Arteries Biomechanics Biomedical Engineering Blood Vessels Coculture Techniques Connexins Data Development Developmental Biology Diameter 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 Muscle Cells 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 Therapeutic Intervention Thick Tissue Engineering Translating Vascular Diseases Vascular Graft Vascular remodeling Vein graft Veins Venous arterial remodeling calponin clinical application decorin design differential expression hemodynamics improved in vivo insight mechanotransduction mouse model notch protein overexpression 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.

总结动脉和静脉在人体生理和血管疾病中起着不同的作用。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。这种分子区分的建立由一系列转录程序协调，这些程序在发育生物学中已经得到了很好的研究。然而，这些EC转录程序如何控制成人血管的结构和功能，以及如何控制成人血管的结构和功能。将这些知识转化为临床应用，如静脉或组织工程移植物适应性，探讨了为了解决这个问题，我们研究了成人动脉与静脉EC的转录谱，并且已经鉴定了几种在动脉中差异表达的关键转录因子， vs.静脉内皮细胞其中，Sox 13和Sox 17在成人动脉内皮细胞中高表达，而在静脉内皮细胞中不表达 EC。我们的初步研究表明，在静脉内皮细胞中过表达Sox 17可以重建所有的细胞因子。已知的动脉标志物，表明Sox 17是成人动脉EC表型的关键调节因子。重要的是， Sox 17诱导多个分子家族（Notch、Ephrin、连接蛋白、PDGF）的表达，这些分子家族可能将来自EC的信号传递给平滑肌细胞（SMC）以调节血管中SMC的表型。EC Sox 17还促进EC-SMC共培养和移植物重塑模型中SMC的收缩表型。上另一方面，在EC中过表达Sox 13促进SMC向血管募集。基于根据这些令人鼓舞的初步数据，我们推测内皮细胞Sox 13/17在细胞凋亡中起协同作用。通过维持成人动脉EC表型和使EC- SMC串扰。为了验证这一假设，我们将研究内皮细胞Sox 13/17如何调节EC， SMC表型及其在血管结构和功能中的作用，使用体外生物工程模型作为以及体内动物模型。