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

• 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
• 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

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.

摘要 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(ECs)表现出不同的分子特征。这种分子区分的建立 是由一系列转录程序编排的，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转录程序是如何控制成人血管结构和功能的，以及如何 将这一知识转化为临床应用，如静脉或组织工程移植物适应正在进行中- 探索过了。为了解决这个问题，我们研究了成人动脉和静脉内皮细胞的转录图谱。 并已确定了几个在动脉中差异表达的关键转录因子 与静脉内皮细胞相比。其中，Sox13和Sox17在成人动脉内皮细胞中高表达，在静脉内皮细胞中不表达 ECS。我们的初步研究表明，在静脉内皮细胞中过表达的Sox17重组了所有 已知的动脉标志物，表明Sox17是成人动脉EC表型的关键调节因子。重要的是 Sox17诱导多种分子家族(Notch、EPhin、Connecexins、PDGF)的表达，这些分子可能 内皮细胞将信号传递给血管内皮细胞，以调节血管中的SMC表型。欧共体 Sox17还可促进EC-SMC共培养的SMC收缩表型和移植物重塑模型。论 另一方面，在内皮细胞中过表达Sox13有助于血管内皮细胞向血管内皮细胞募集。基于 这些令人鼓舞的初步数据，我们假设内皮细胞Sox13/17在 维持成人动脉内皮细胞表型和参与内皮细胞功能的动态平衡调节 SMC相声。为了验证这一假说，我们将研究内皮细胞Sox13/17是如何调节EC和 用体外生物工程模型研究SMC表型及其在血管结构和功能中的作用 以及活体动物模型。