Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension.
Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension.
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DOI：
10.3389/fcvm.2023.1274033
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发表时间：
2023
影响因子：
3.6
通讯作者：
Klinger, James R.
中科院分区：
文献类型：
--
作者：
Simmons Beck, Robert;Liang, Olin D.;Klinger, James R.
关键词：
肺动脉高压（PAH）是一种进行性疾病，其特征是远端肺循环的闭塞性血管病变。尽管我们对病理生理学的理解取得了重大进展，但目前批准的 PAH 药物治疗主要起肺血管扩张剂的作用，未能解决导致疾病发生和进展的潜在过程。内皮因应激、损伤或生理刺激而失调，随后免疫细胞在血管周围浸润，在 PAH 的肺血管重塑中发挥着重要作用。在过去的几十年里，我们对内皮细胞失调的理解不断发展，并揭示了许多在血管稳态和血管生成中发挥重要作用的转录因子。在这篇综述中，我们研究了两个这样的因素，SOX17 及其下游靶标之一 RUNX1，以及暗示它们在 PAH 发病机制中作用的新数据。我们回顾了它们的发现并讨论了它们在血管生成和肺血管发育中的功能，包括它们在内皮到造血转变（EHT）中的作用以及它们驱动祖干细胞走向内皮或骨髓命运的能力。我们还总结了 Sox17 突变与 PAH 发病风险增加相关的研究数据，以及表明 Sox17 和 Runx1 与 PAH 发病机制有关的研究数据。最后，我们回顾了我们实验室最近的研究结果，证明通过删除内皮细胞或骨髓细胞中的 RUNX1 表达或使用 RUNX1 抑制剂，可以在 PAH 动物模型中预防和逆转肺动脉高压。通过 SOX17 和 RUNX1 的视角研究 PAH，我们希望阐明这些转录因子在血管稳态和内皮失调中的作用、它们对 PAH 肺血管重塑的贡献，以及它们作为治疗这种破坏性疾病的新治疗靶点的潜力。
Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by an obliterative vasculopathy of the distal pulmonary circulation. Despite significant progress in our understanding of the pathophysiology, currently approved medical therapies for PAH act primarily as pulmonary vasodilators and fail to address the underlying processes that lead to the development and progression of the disease. Endothelial dysregulation in response to stress, injury or physiologic stimuli followed by perivascular infiltration of immune cells plays a prominent role in the pulmonary vascular remodeling of PAH. Over the last few decades, our understanding of endothelial cell dysregulation has evolved and brought to light a number of transcription factors that play important roles in vascular homeostasis and angiogenesis. In this review, we examine two such factors, SOX17 and one of its downstream targets, RUNX1 and the emerging data that implicate their roles in the pathogenesis of PAH. We review their discovery and discuss their function in angiogenesis and lung vascular development including their roles in endothelial to hematopoietic transition (EHT) and their ability to drive progenitor stem cells toward an endothelial or myeloid fate. We also summarize the data from studies that link mutations in Sox17 with an increased risk of developing PAH and studies that implicate Sox17 and Runx1 in the pathogenesis of PAH. Finally, we review the results of recent studies from our lab demonstrating the efficacy of preventing and reversing pulmonary hypertension in animal models of PAH by deleting RUNX1 expression in endothelial or myeloid cells or by the use of RUNX1 inhibitors. By investigating PAH through the lens of SOX17 and RUNX1 we hope to shed light on the role of these transcription factors in vascular homeostasis and endothelial dysregulation, their contribution to pulmonary vascular remodeling in PAH, and their potential as novel therapeutic targets for treating this devastating disease.
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影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
6
作者：
Hu Y;Chi L;Kuebler WM;Goldenberg NM
通讯作者：
Goldenberg NM
影响因子：
16.6
作者：
Gräf S;Haimel M;Bleda M;Hadinnapola C;Southgate L;Li W;Hodgson J;Liu B;Salmon RM;Southwood M;Machado RD;Martin JM;Treacy CM;Yates K;Daugherty LC;Shamardina O;Whitehorn D;Holden S;Aldred M;Bogaard HJ;Church C;Coghlan G;Condliffe R;Corris PA;Danesino C;Eyries M;Gall H;Ghio S;Ghofrani HA;Gibbs JSR;Girerd B;Houweling AC;Howard L;Humbert M;Kiely DG;Kovacs G;MacKenzie Ross RV;Moledina S;Montani D;Newnham M;Olschewski A;Olschewski H;Peacock AJ;Pepke-Zaba J;Prokopenko I;Rhodes CJ;Scelsi L;Seeger W;Soubrier F;Stein DF;Suntharalingam J;Swietlik EM;Toshner MR;van Heel DA;Vonk Noordegraaf A;Waisfisz Q;Wharton J;Wort SJ;Ouwehand WH;Soranzo N;Lawrie A;Upton PD;Wilkins MR;Trembath RC;Morrell NW
通讯作者：
Morrell NW
Sox17 促进细胞周期进程并抑制 TGF-β/Smad3 信号传导以启动呼吸道上皮中的祖细胞行为。
影响因子：
3.7
作者：
Lange AW;Keiser AR;Wells JM;Zorn AM;Whitsett JA
通讯作者：
Whitsett JA
影响因子：
20.3
作者：
Asosingh, Kewal;Farha, Samar;Erzurum, Serpil C.
通讯作者：
Erzurum, Serpil C.