Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway

Wu, Jiunn‐Ren; Yeh, Jwu‐Lai; Liou, Shu-Fen; Dai, Zen‐Kong; Wu, Bin–Nan; Hsu, Jong‐Hau

doi:10.7150/ijbs.16430

Cited by 30 publications

(26 citation statements)

References 36 publications

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“…Many studies suggest that Notch is necessary for maintaining VSMCs in a contractile/quiescent phenotype. In rat VSMCs, the IL-1β-induced secretory/migrating phenotype is blunted by Notch-3 overexpression and enhanced by treatment with DAPT, a γ-secretase inhibitor [259] but, contrary to this finding, DAPT also seems to prevent SMC migration and proliferation induced by AngII [260].…”

Section: Notch In Vascular Smooth Muscle Cellsmentioning

confidence: 69%

The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

Aquila

Marracino

Martino

et al. 2019

Oxidative Medicine and Cellular Longevity

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Despite the currently available pharmacotherapies, today, thirty percent of worldwide deaths are due to cardiovascular diseases (CVDs), whose primary cause is atherosclerosis, an inflammatory disorder characterized by the buildup of lipid deposits on the inside of arteries. Multiple cellular signaling pathways have been shown to be involved in the processes underlying atherosclerosis, and evidence has been accumulating for the crucial role of Notch receptors in regulating the functions of the diverse cell types involved in atherosclerosis onset and progression. Several classes of nutraceuticals have potential benefits for the prevention and treatment of atherosclerosis and CVDs, some of which could in part be due to their ability to modulate the Notch pathway. In this review, we summarize the current state of knowledge on the role of Notch in vascular health and its modulation by nutraceuticals for the prevention of atherosclerosis and/or treatment of related CVDs.

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Section: Notch In Vascular Smooth Muscle Cellsmentioning

confidence: 69%

The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

Aquila

Marracino

Martino

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…ERK1/2 has been shown to be an endogenous negative regulator of the γ-secretase activity by phosphorylating nicastrin, an essential component of γ-secretase; while presenilin, another key component of γ-secretase activity has been shown to be able to activate PI3K and ERK1/2 [48,49]. Using ductus ateriosus smooth muscle cells, Wu and colleagues demonstrated that DAPT inhibits cell proliferation by not only inhibiting ERK1/2 and Akt phosphorylation but also by promoting cell cycle arrest in the G0/G1-phase [50]. Collectively, these effects of single stimulation of mCRP, FGF-2 and their combination mCRP with FGF-2 on EC proliferation confirm the theory that growth factors display additive and even synergistic characteristics during early stages of angiogenesis, with the combination of at least two growth factors displaying the highest proliferation rate [51].…”

Section: Discussionmentioning

confidence: 99%

Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

Boras¹,

Slevin²,

Gilmore³

et al. 2018

Eur J Exp Bio

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Excessive angiogenesis (i.e. neovascularization) in atherosclerotic lesions, sites of dissociation of the inflammatory biomarker pentameric C-reactive protein (pCRP) into monomeric CRP (mCRP), represents a focus of plaque instability with haemorrhagic complications. We previously demonstrated mCRP pro-angiogenic effects on cultured aortic endothelial cells. However, mCRP effects in combination with FGF-2, pro-angiogenic factor released by activated macrophages infiltrating developing lesions, have not yet been described. Here, we examined in vitro the angiogenic capabilities of mCRP combined with FGF-2 by performing endothelial cell proliferation, migration, and differentiation including tube formation and spheroid sprouting assays. The signaling pathways were also investigated by Western blotting and all the cell-based assays were used with or without pharmacological inhibitors of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K) and γ-secretase, considered as key regulators of angiogenesis. We showed that mCRP-induced endothelial cell proliferation and migration required activation of PI3K pathway. MAPK pathway was essential in mCRP-induced endothelial cell proliferation and spheroid sprouting while γ-secretase activity was indispensable for mCRP-induced tube formation only. MAPK pathway was required in all FGF-2-stimulated angiogenic assays whereas γ-secretase slightly inhibited FGF-2 angiogenic effects. PI3K pathway was necessary for FGF-2 angiogenic activities except for cell differentiation. In most of the assays, the additive pro-angiogenic effects of mCRP combined to FGF-2 were mainly attenuated by PI3K and MAPK inhibitors. Altogether, mCRP and FGF-2 have common angiogenic signaling pathways through PI3K and MAPK. Thus, the therapeutic use of PI3K and MAPK inhibitors may inhibit this increased vascularization whilst reducing the haemorrhagic complications from unstable plaques.

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“…The up-regulation of IL-15 in the ductus is mediated through the prostaglandin pathway. IL-15 upregulates the expression of EP 4 mRNA, as well as stimulating angiogenesis through binding to endothelial cells ( 91 ). In late gestation, several factors try to promote the structural closure of the ductus in preparation for the postnatal life and IL-15 may balance this tendency by a counteractive mechanism ( 92 ).…”

Section: Anatomic Closure and Remodelingmentioning

confidence: 99%

“…A decrease in the number of Notch receptors in SMCs is associated with downregulation of gene expressions related to contractile elements ( 84 ). Notch signaling is required for contractile SMC differentiation in mice ( 91 ).…”

Section: Anatomic Closure and Remodelingmentioning

confidence: 99%

“…Leukocyte interactions with P-selectin and Intercellular Adhesion Molecule-1 (ICAM-1) is necessary for recruitment when physiologic shear forces are present and this interaction is only possible when the flow is very slow. Therefore, leukocytes can adhere to the ductal wall only after vasoconstriction and loss of ductal flow has occurred ( 99 , 100 ) Monocytes and phagocytes adhere to the wall of the ductus via vascular cell adhesion molecule-1 (VCAM-1), whose expression increase after birth ( 7 , 91 ). VEGF is a direct chemoattractant for monocytes ( 101 ).…”

Section: Anatomic Closure and Remodelingmentioning

confidence: 99%

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Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants

Ovalı

2020

Front. Pediatr.

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Failure of ductus arteriosus closure after preterm birth is associated with significant morbidities. Ductal closure requires and is regulated by a complex interplay of molecular and mechanical mechanisms with underlying genetic factors. In utero patency of the ductus is maintained by low oxygen tension, high levels of prostaglandins, nitric oxide and carbon monoxide. After birth, ductal closure occurs first by functional closure, followed by anatomical remodeling. High oxygen tension and decreased prostaglandin levels mediated by numerous factors including potassium channels, endothelin-1, isoprostanes lead to the contraction of the ductus. Bradykinin and corticosteroids also induce ductal constriction by attenuating the sensitivity of the ductus to PGE2. Smooth muscle cells of the ductus can sense oxygen through a mitochondrial network by the role of Rho-kinase pathway which ends up with increased intracellular calcium levels and contraction of myosin light chains. Anatomical closure of the ductus is also complex with various mechanisms such as migration and proliferation of smooth muscle cells, extracellular matrix production, endothelial cell proliferation which mediate cushion formation with the interaction of blood cells. Regulation of vessel walls is affected by retinoic acid, TGF-β1, notch signaling, hyaluronan, fibronectin, chondroitin sulfate, elastin, and vascular endothelial cell growth factor (VEGF). Formation of the platelet plug facilitates luminal remodeling by the obstruction of the constricted ductal lumen. Vasa vasorum are more pronounced in the term ductus but are less active in the preterm ductus. More than 100 genes are effective in the prostaglandin pathway or in vascular smooth muscle development and structure may affect the patency of ductus. Hemodynamic changes after birth including fluid load and flow characteristics as well as shear forces within the ductus also stimulate closure. Current pharmacological treatment for the closure of a patent ductus is based on the blockage of the prostaglandin pathway mainly through COX or POX inhibition, albeit with some limitations and side effects. Further research for new agents aiming ductal closure should focus on a clear understanding of vascular biology of the ductus.

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Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway

Cited by 30 publications

References 36 publications

The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants

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