Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.
Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.
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激活小鼠血管生态位中的 NO-sGC 串扰可促进血管完整性并减轻急性肺损伤
DOI：
10.1084/jem.20211422
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发表时间：
2023-02-06
影响因子：
15.3
通讯作者：
Hu, Junhao
中科院分区：
文献类型：
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作者：
He, Hao;Yang, Wu;Su, Nan;Zhang, Chuankai;Dai, Jianing;Han, Feng;Singhal, Mahak;Bai, Wenjuan;Zhu, Xiaolan;Zhu, Jing;Liu, Zhen;Xia, Wencheng;Liu, Xiaoting;Zhang, Chonghe;Jiang, Kai;Huang, Wenhui;Chen, Dan;Wang, Zhaoyin;He, Xueyang;Kirchhoff, Frank;Li, Zhenyu;Liu, Cong;Huan, Jingning;Wang, Xiaohong;Wei, Wu;Wang, Jing;Augustin, Hellmut G;Hu, Junhao
通过系统性 EC-周细胞串扰分析，本研究确定 NO-sGC 是介导肺血管系统中 EC-周细胞通讯的关键信号，并证明 NO-sGC 信号的药理激活可促进血管完整性并减轻炎症引起的肺损伤。内皮细胞 (EC) 和周细胞相互作用的破坏导致急性肺损伤 (ALI) 中的血管渗漏。然而，介导 EC-周细胞串扰的分子信号尚未得到系统研究，并且是否可以采用针对这种串扰来对抗 ALI 仍然难以捉摸。通过对健康肺和受到 LPS 攻击的肺进行比较全基因组 EC-周细胞串扰分析，我们发现内皮一氧化氮和周细胞可溶性鸟苷酸环化酶 (NO-sGC) 之间的串扰在 ALI 中受损。事实上，刺激 NO-sGC 通路可以促进血管完整性，减少肺水肿和炎症引起的肺损伤，而周细胞特异性 sGC 敲除则消除了这种保护作用。从机制上讲，sGC 激活通过抑制 VASP 依赖性 F-肌动蛋白形成和 MRTFA/SRF 依赖性与细胞骨架重排相关的基因从头合成来抑制周细胞中的细胞骨架重排，从而稳定 EC-周细胞相互作用。总的来说，我们的数据表明，血管生态位中 NO-sGC 串扰受损会导致血管通透性升高，而这种串扰的药理学激活代表了 ALI 的一种有前途的转化疗法。
Using systemic EC–pericyte crosstalk analysis, this study identifies the NO–sGC as a key signaling that mediates EC–pericyte communication in the lung vasculature and demonstrates that pharmacological activation of the NO–sGC signaling promotes vascular integrity and mitigates inflammation-induced lung injury. Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC–pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC–pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO–sGC) is impaired in ALI. Indeed, stimulating the NO–sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC–pericyte interactions. Collectively, our data demonstrate that impaired NO–sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.