A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells Is the Cell of Origin for Occlusive Pulmonary Vascular Lesions.
A Notch3-Marked Subpopulation of Vascular Smooth Muscle Cells Is the Cell of Origin for Occlusive Pulmonary Vascular Lesions.
复制标题
Notch3 标记的血管平滑肌细胞亚群是闭塞性肺血管病变的起源细胞。
DOI：
10.1161/circulationaha.120.045750
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发表时间：
2020-10-20
期刊：
影响因子：
37.8
通讯作者：
Kumar ME
中科院分区：
文献类型：
--
作者：
Steffes LC;Froistad AA;Andruska A;Boehm M;McGlynn M;Zhang F;Zhang W;Hou D;Tian X;Miquerol L;Nadeau K;Metzger RJ;Spiekerkoetter E;Kumar ME
肺动脉高压（PAH）是一种以严重血管重塑为特征的致死性疾病，其中肺动脉由于中膜增厚和新生内膜病变闭塞而狭窄，导致肺血管阻力升高和右心衰竭。靶向新生内膜的治疗将代表PAH治疗的重大进展，然而，我们对驱动新生内膜形成的细胞事件以及控制它们的分子途径的理解仍然有限。我们在一个稳健的慢性炎症性肺动脉高压小鼠模型中全面绘制了肺动脉的逐步重塑。该模型显示了人类疾病的病理特征，包括右心室压力增加、中膜增厚、新生内膜病变形成、弹性蛋白分解、支气管循环内吻合增加和血管周围炎症。使用遗传谱系追踪、克隆分析、多重原位杂交、免疫染色、深度共聚焦成像和分阶段药理学抑制，我们定义了血管重塑每个阶段的细胞行为，并确定了新生内膜形成所需的途径。新生内膜来源于平滑肌细胞（SMC），而不是内皮细胞。中膜平滑肌细胞广泛增殖以覆盖中膜，之后选择少量平滑肌细胞建立新生内膜。这些新生内膜创始者细胞随后经历大量克隆扩增，形成闭塞性新生内膜病变。正常肺动脉SMC群体是异质性的，我们确定了一个Notch3标记的SMC的少数子集作为主要的新生内膜细胞的起源。Notch信号传导是选择新生内膜创始细胞所特别需要的，并且Notch抑制显著改善患有肺动脉高压的动物的肺动脉压力。这项工作描述了第一个非遗传驱动的PH小鼠模型，该模型在肺血管床上产生了强大的弥漫性闭塞性新生内膜病变，并且在定型的时间范围内这样做。我们揭示了中膜增厚和新生内膜形成的不同细胞和分子机制，并强调了肺动脉SMC内新的转录、行为和致病异质性。在该模型中，炎症足以产生人类PAH的特征性血管病理和生理指标。我们希望，确定调节血管重塑每个阶段的分子线索将为PAH治疗的治疗进展开辟新的途径。
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by profound vascular remodeling in which pulmonary arteries narrow due to medial thickening and occlusion by neointimal lesions, resulting in elevated pulmonary vascular resistance and right heart failure. Therapies targeting the neointima would represent a significant advance in PAH treatment, however our understanding of the cellular events driving neointima formation, and the molecular pathways that control them, remains limited. We comprehensively map the stepwise remodeling of pulmonary arteries in a robust, chronic inflammatory mouse model of pulmonary hypertension. This model demonstrates pathologic features of the human disease, including increased right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation, and perivascular inflammation. Using genetic lineage tracing, clonal analysis, multiplexed in situ hybridization, immunostaining, deep confocal imaging and staged pharmacologic inhibition we define the cell behaviors underlying each stage of vascular remodeling and identify a pathway required for neointima formation. Neointima arises from smooth muscle cells (SMCs) and not endothelium. Medial SMCs proliferate broadly to thicken the media, after which a small number of SMCs are selected to establish the neointima. These neointimal founder cells subsequently undergoing massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery SMC population is heterogeneous and we identify a Notch3-marked minority subset of SMCs as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension. This work describes the first nongenetically driven murine model of PH that generates robust and diffuse occlusive neointimal lesions across the pulmonary vascular bed and does so in a stereotyped timeframe. We uncover distinct cellular and molecular mechanisms underlying medial thickening and neointima formation and highlight novel transcriptional, behavioral and pathogenic heterogeneity within pulmonary artery SMCs. In this model, inflammation is sufficient to generate characteristic vascular pathologies and physiologic measures of human PAH. We hope that identifying the molecular cues regulating each stage of vascular remodeling will open new avenues for therapeutic advancements in the treatment of PAH.