KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway

Xu, Hongyuan; Huo, Ran; Li, Hao; Jiao, Yuming; Weng, Jian-Cong; Wang, Jie; Yan, Zihan; Zhang, Junze; Zhao, Shufang; He, Qiheng; Sun, Yingfan; Wang, Shuo; Cao, Yong

doi:10.1136/svn-2022-001700

Cited by 6 publications

(3 citation statements)

References 36 publications

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“…Expression of KRAS G12V in HUVECs up-regulates Notch pathway genes, e.g., DLL4 , JAG1 , JAG2 , NOTCH1 , HES1 , and HEY2 ( 8 , 45 ). In another study, expression of KRAS G12D also up-regulates Notch2, Notch4, hairy/enhancer-of-split related with YRPW motif 1 (HEY1), and HEY2 in HUVECs ( 45 , 46 ). However, there were no detectable changes in the expression of Notch ligand Dll4 in zebrafish expressing KRAS G12D in the endothelium ( 47 ).…”

Section: Discussionmentioning

confidence: 93%

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation

et al. 2023

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Mechanisms underlying arteriovenous malformations (AVMs) are poorly understood. Using mice with endothelial cell (EC) expression of constitutively active Notch4 (Notch4* EC ), we show decreased arteriolar tone in vivo during brain AVM initiation. Reduced vascular tone is a primary effect of Notch4* EC , as isolated pial arteries from asymptomatic mice exhibited reduced pressure-induced arterial tone ex vivo. The nitric oxide (NO) synthase (NOS) inhibitor NG-nitro- l -arginine (L-NNA) corrected vascular tone defects in both assays. L-NNA treatment or endothelial NOS ( eNOS ) gene deletion, either globally or specifically in ECs, attenuated AVM initiation, assessed by decreased AVM diameter and delayed time to moribund. Administering nitroxide antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl also attenuated AVM initiation. Increased NOS-dependent production of hydrogen peroxide, but not NO, superoxide, or peroxynitrite was detected in isolated Notch4* EC brain vessels during AVM initiation. Our data suggest that eNOS is involved in Notch4* EC -mediated AVM formation by up-regulating hydrogen peroxide and reducing vascular tone, thereby permitting AVM initiation and progression.

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Section: Discussionmentioning

confidence: 93%

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation

et al. 2023

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“…20 The common inflammatory pathway and genetic alteration for AVM pathogenesis is shown in Figures 1 and 2 proliferation, migration, and tube formation. 24…”

Section: Molecular and Genetic Inflammation Mechanisms In Avmmentioning

confidence: 99%

“…TGF‐β/ALK1 signaling activates SMAD2/3, which stimulates endothelial cell migration, tube formation, and proliferation. Meanwhile, TGF‐β/ALK5 signaling activates SMAD2/3 phosphorylation and inhibits angiogenesis by blocking endothelial cell proliferation, migration, and tube formation 24 …”

Section: Molecular and Genetic Inflammation Mechanisms In Avmmentioning

confidence: 99%

Key biomarkers in cerebral arteriovenous malformations: Updated review

Tanzadehpanah

Modaghegh

Mahaki

2023

The Journal of Gene Medicine

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The formation of vascular networks consisting of arteries, capillaries, and veins is vital in embryogenesis. It is also crucial in adulthood for the formation of a functional vasculature. Cerebral arteriovenous malformations (CAVMs) are linked with a remarkable risk of intracerebral hemorrhage because arterial blood is directly shunted into the veins before the arterial blood pressure is dissipated. The underlying mechanisms responsible for arteriovenous malformation (AVM) growth, progression, and rupture are not fully known, yet the critical role of inflammation in AVM pathogenesis has been noted. The proinflammatory cytokines are upregulated in CAVM, which stimulates overexpression of cell adhesion molecules in endothelial cells (ECs), leading to improved leukocyte recruitment. It is well‐known that metalloproteinase‐9 secretion by leukocytes disrupts CAVM walls resulting in rupture. Moreover, inflammation alters the angioarchitecture of CAVMs by upregulating angiogenic factors impacting the apoptosis, migration, and proliferation of ECs. A better understanding of the molecular signature of CAVM might allow us to identify biomarkers predicting this complication, acting as a goal for further investigations that may be potentially targeted in gene therapy. The present review is focused on the numerous studies conducted on the molecular signature of CAVM and the associated hemorrhage. The association of numerous molecular signatures with a higher risk of CAVM rupture is shown through inducing proinflammatory mediators, as well as growth factors signaling, Ras‐mitogen‐activated protein kinase‐extracellular signal‐regulated kinase, and NOTCH pathways, which are accompanied by cellular level inflammation and endothelial alterations resulting in vascular wall instability. According to the studies, it is assumed that matrix metalloproteinase, interleukin‐6, and vascular endothelial growth factor are the biomarkers most associated with CAVM and the rate of hemorrhage, as well as diagnostic methods, with respect to enhancing the patient‐specific risk estimation and improving treatment choices.

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Exosomes on the development and progression of renal fibrosis

Wang,

Chen,

et al. 2024

Cell Proliferation

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Renal fibrosis is a prevalent pathological alteration that occurs throughout the progression of primary and secondary renal disorders towards end‐stage renal disease. As a complex and irreversible pathophysiological phenomenon, it includes a sequence of intricate regulatory processes at the molecular and cellular levels. Exosomes are a distinct category of extracellular vesicles that play a crucial role in facilitating intercellular communication. Multiple pathways are regulated by exosomes produced by various cell types, including tubular epithelial cells and mesenchymal stem cells, in the context of renal fibrosis. Furthermore, research has shown that exosomes present in bodily fluids, including urine and blood, may be indicators of renal fibrosis. However, the regulatory mechanism of exosomes in renal fibrosis has not been fully elucidated. This article reviewed and analysed the various mechanisms by which exosomes regulate renal fibrosis, which may provide new ideas for further study of the pathophysiological process of renal fibrosis and targeted treatment of renal fibrosis with exosomes.

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KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway

Cited by 6 publications

References 36 publications

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation

Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation

Key biomarkers in cerebral arteriovenous malformations: Updated review

Exosomes on the development and progression of renal fibrosis

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