Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice.
Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice.
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内皮Notch激活重塑肝窦内皮细胞的血管分泌，加剧小鼠肝纤维化并钝化再生
DOI：
10.1002/hep.29834
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Duan JL;Ruan B;Yan XC;Liang L;Song P;Yang ZY;Liu Y;Dou KF;Han H;Wang L
肝窦内皮细胞（LSECs）通过血管分泌因子调节肝脏稳态和疾病。Notch在内皮细胞（EC）中至关重要。在当前的研究中，Notch信号传导通过Notch胞内结构域（NIC）的可诱导EC特异性表达来激活。我们发现内皮Notch激活破坏了肝脏的稳态。Notch激活导致开窗减少和基底膜增加，以及LSEC相关基因减少和连续EC相关基因增加的基因表达谱，表明LSEC去分化。一致地，内皮Notch激活增强CCl 4诱导的肝纤维化（HF）。Notch激活减弱了内皮型一氧化氮合酶（eNOS）/可溶性鸟苷酸环化酶（sGC）信号传导，3-（5′-羟甲基-2 ′-呋喃基）-1-苄基吲唑（YC-1）激活sGC逆转了去分化表型。此外，Notch激活通过下调关键的肝细胞有丝分裂原（包括Wnt 2a、Wnt 9 b和肝细胞生长因子（HGF）），破坏了LSEC的肝细胞支持血管分泌特征。这导致在静止和再生条件下肝细胞增殖受损。尽管Wnt 2a和Wnt 9 b的表达依赖于eNOS-sGC信号传导，但HGF表达不受sGC激活剂的拯救，这表明LSEC维持肝细胞稳态的异质性机制。结论：内皮Notch激活通过eNOS‐sGC信号传导导致LSEC去分化和加速肝纤维化，并改变LSEC的血管分泌谱以损害肝细胞增殖和肝再生（LR）。（Hepatology 2018）。
Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC‐specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC‐associated genes and increased continuous EC‐associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl4. Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte‐supporting angiocrine profile of LSECs by down‐regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS‐sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis. Conclusion: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS‐sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (Hepatology 2018).
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影响因子：
13.5
作者：
DeLeve, Laurie D.
通讯作者：
DeLeve, Laurie D.
内皮缺口信号传导对于预防小鼠肝血管畸形至关重要。
DOI：
10.1002/hep.28713
发表时间：
2016-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Cuervo H;Nielsen CM;Simonetto DA;Ferrell L;Shah VH;Wang RA
通讯作者：
Wang RA
影响因子：
25.7
作者：
Marrone G;Shah VH;Gracia-Sancho J
通讯作者：
Gracia-Sancho J
影响因子：
25.7
作者：
Marrone, Giusi;Russo, Lucia;Gracia-Sancho, Jorge
通讯作者：
Gracia-Sancho, Jorge
影响因子：
11.2
作者：
Patenaude, Alexandre;Fuller, Megan;Karsan, Aly
通讯作者：
Karsan, Aly