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河马信号通路在脑动静脉畸形中的作用:栓塞后重塑的分子见解

The Role of Hippo Signaling in Brain Arteriovenous Malformations: Molecular Insights into Post-Embolization Remodeling.

作者信息

Neyazi Belal, Swiatek Vanessa Magdalena, Karimpour Mohammad Ali, Stassen Sarah, Stein Klaus-Peter, Rashidi Ali, Dumitru Claudia Alexandra, Sandalcioglu I Erol

机构信息

Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany.

出版信息

Int J Mol Sci. 2025 Apr 17;26(8):3791. doi: 10.3390/ijms26083791.


DOI:10.3390/ijms26083791
PMID:40332417
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12028238/
Abstract

Brain arteriovenous malformations (bAVMs) are complex vascular lesions with significant clinical risks. The Hippo signaling pathway, particularly its downstream effector YAP, plays a crucial role in angiogenesis and vascular remodeling. This study investigates the role of YAP and related molecular markers in bAVMs, focusing on the effects of embolization. Immunohistochemical analysis was conducted on tissue samples from bAVM patients (n = 127), as well as on healthy blood vessels (n = 17). YAP, HIF-1α, FGFR1, CTGF, and CYR61 expression were quantified and correlated with clinical parameters. Results: In healthy vessels, YAP exhibited nuclear localization in (sub)endothelial cells and the tunica media, while CTGF and CYR61 were detected in the cytoplasm and extracellular matrix. The expression of YAP, CTGF, and CYR61 was significantly lower in bAVM tissues. Embolized bAVMs exhibited significantly higher expression of YAP, CTGF, and CYR61 compared to non-embolized tissues, suggesting a link between embolization and pro-angiogenic signaling. Additionally, FGFR1 was upregulated in embolized tissues. These results suggest that upregulation of YAP expression via the Hippo pathway might play a key role in bAVM pathophysiology. Embolization may further promote vascular remodeling. Dysregulation of YAP and related molecules in bAVMs warrants further studies to explore potential therapeutic strategies targeting the Hippo pathway.

摘要

脑动静脉畸形(bAVM)是具有重大临床风险的复杂血管病变。 Hippo信号通路,尤其是其下游效应因子YAP,在血管生成和血管重塑中起关键作用。本研究调查YAP及相关分子标志物在bAVM中的作用,重点关注栓塞的影响。对bAVM患者(n = 127)的组织样本以及健康血管(n = 17)进行免疫组织化学分析。对YAP、HIF-1α、FGFR1、CTGF和CYR61的表达进行定量,并与临床参数进行关联分析。结果:在健康血管中,YAP在内皮细胞和(或)中膜细胞中呈核定位,而CTGF和CYR61在细胞质和细胞外基质中被检测到。bAVM组织中YAP、CTGF和CYR61的表达显著降低。与未栓塞组织相比,栓塞后的bAVM组织中YAP、CTGF和CYR61的表达显著升高,提示栓塞与促血管生成信号之间存在联系。此外,FGFR1在栓塞组织中上调。这些结果表明,通过Hippo途径上调YAP表达可能在bAVM病理生理学中起关键作用。栓塞可能进一步促进血管重塑。bAVM中YAP及相关分子的失调值得进一步研究,以探索针对Hippo途径的潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/1a17b4c14139/ijms-26-03791-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/2f323eaca9d4/ijms-26-03791-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/a55982b720df/ijms-26-03791-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/9b18cc738b35/ijms-26-03791-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/87aed0291dfe/ijms-26-03791-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/a9cd6a30984c/ijms-26-03791-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/1ae832b328fb/ijms-26-03791-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/36d8e33b3edb/ijms-26-03791-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/1a17b4c14139/ijms-26-03791-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/2f323eaca9d4/ijms-26-03791-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/a55982b720df/ijms-26-03791-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/9b18cc738b35/ijms-26-03791-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/87aed0291dfe/ijms-26-03791-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/a9cd6a30984c/ijms-26-03791-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/1ae832b328fb/ijms-26-03791-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/36d8e33b3edb/ijms-26-03791-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36b4/12028238/1a17b4c14139/ijms-26-03791-g008.jpg

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[7]
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本文引用的文献

[1]
Vascular stability of brain arteriovenous malformations after partial embolization.

CNS Neurosci Ther. 2024-3

[2]
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[3]
YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells.

Anal Cell Pathol (Amst). 2022

[4]
Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

Circulation. 2021-9-7

[5]
Oscillatory shear stress promotes angiogenic effects in arteriovenous malformations endothelial cells.

Mol Med. 2021-3-31

[6]
Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer.

Nat Biomed Eng. 2021-1

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Acta Pharm Sin B. 2020-6

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Nonlinear hydrodynamic instability and turbulence in pulsatile flow.

Proc Natl Acad Sci U S A. 2020-5-11

[9]
YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation.

Nat Commun. 2020-1-3

[10]
Age-dependent changes of collagen alpha-2(IV) expression in the extracellular matrix of brain arteriovenous malformations.

Clin Neurol Neurosurg. 2020-2

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