Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics.

IF 35.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation Pub Date : 2025-02-10 DOI:10.1161/CIRCULATIONAHA.124.070782

Ximeng Han, Yi Li, Enci Wang, Huan Zhu, Xiuzhen Huang, Wenjuan Pu, Mingjun Zhang, Kuo Liu, Huan Zhao, Zixin Liu, Yufei Zhao, Linghong Shen, Yan Li, Xiao Yang, Qing-Dong Wang, Xin Ma, Ruling Shen, Kathy Lui, Lixin Wang, Ben He, Bin Zhou

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引用次数: 0

Abstract

Background: The developmental diversity among smooth muscle cells (SMCs) plays a crucial role in segment-specific aortic diseases. However, traditional genetic approaches are inadequate for enabling in vivo analysis of disease susceptibility associated with cellular origin. There is an urgent need to build genetic technologies that target different developmental origins to investigate the mechanisms of aortopathies, thereby facilitating the development of effective therapeutics.

Methods: To address this challenge, we developed an advanced dual recombinase-mediated intersectional genetic system, specifically designed to precisely target SMCs from various developmental origins in mice. Specifically, we used Isl1-Dre, Wnt1-Dre, Meox1-DreER, and Upk3b-Dre to target SMC progenitors from the second heart field, cardiac neural crest, somites, and mesothelium, respectively. This system was combined with single-cell RNA sequencing to investigate the impact of TGF-β (transforming growth factor-β) signaling in different segments of the aorta by selectively knocking out Tgfbr2 in the ascending aorta and Smad4 in the aortic arch, respectively.

Results: Through intersectional genetic approaches, we use the Myh11-Cre(ER) driver along with origin-specific Dre drivers to trace cells of diverse developmental origins within the SMC population. We found that a deficiency of Tgfbr2 in SMCs of the ascending aorta leads to aneurysm formation in this specific region. We also demonstrate the critical role of Smad4 in preserving aortic wall integrity and homeostasis in SMCs of the aortic arch.

Conclusions: Our approach to genetically targeting SMC subtypes provides a novel platform for exploring origin-dependent or location-specific aortic vascular diseases. This genetic system enables comprehensive analysis of contributions from different cell lineages to SMC behavior and pathology, thereby paving the way for targeted research and therapeutic interventions in the future.

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背景：平滑肌细胞（SMC）的发育多样性在特异性主动脉疾病中起着至关重要的作用。然而，传统的遗传方法不足以在体内分析与细胞起源相关的疾病易感性。目前迫切需要建立针对不同发育起源的基因技术，以研究主动脉疾病的机制，从而促进有效疗法的开发：为了应对这一挑战，我们开发了一种先进的双重组酶介导的交叉遗传系统，专门用于精确靶向小鼠不同发育起源的SMC。具体来说，我们利用Isl1-Dre、Wnt1-Dre、Meox1-DreER和Upk3b-Dre分别靶向来自第二心田、心脏神经嵴、体节和间皮层的SMC祖细胞。该系统与单细胞RNA测序相结合，通过选择性敲除升主动脉的Tgfbr2和主动脉弓的Smad4，分别研究了TGF-β（转化生长因子-β）信号在主动脉不同节段的影响：通过交叉遗传学方法，我们使用Myh11-Cre(ER)驱动程序和起源特异性Dre驱动程序来追踪SMC群体中不同发育起源的细胞。我们发现，升主动脉 SMC 中 Tgfbr2 的缺乏会导致该特定区域动脉瘤的形成。我们还证明了 Smad4 在维护主动脉壁完整性和主动脉弓 SMC 的平衡方面的关键作用：我们针对 SMC 亚型的遗传方法为探索起源依赖性或位置特异性主动脉血管疾病提供了一个新平台。这种基因系统能全面分析不同细胞系对 SMC 行为和病理的贡献，从而为未来的定向研究和治疗干预铺平道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation 医学-外周血管病

CiteScore

45.70

自引率

2.10%

发文量

1473

审稿时长

2 months

期刊介绍： Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.