Abstract 120: Notch Signaling Negatively Regulates Vascular Endothelial Cell Senescence

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yohko Yoshida ◽  
Tohru Minamino
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Notch Signaling ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cell ◽  
Notch Pathway ◽  
Cell Senescence ◽  
Premature Senescence ◽  
Over Expression ◽  
Map Kinase Phosphatase

Accumulation of senescent vascular cells occurs in aged vessels, which leads to an increase of inflammation and a decline of regenerative potential, thereby promoting vascular dysfunction and atherosclerosis. However, the molecular mechanisms of these age-related changes remain unclear. The Notch pathway is a highly conserved signaling that controls cell fate determination and differentiation during the development of various tissues. In adults, Notch signaling has been reported to be essential for neovascularization and is implicated with the age-associated conditions such as cancer, neuronal disorder and impaired regeneration of skeletal muscle. Here, we show that Notch signaling has a crucial role in endothelial cell senescence. We found that inhibition of Notch signaling, using short hairpin RNA (shRNA) targeting Notch1, reduced the maximum population doublings of human umbilical vein endothelial cells (HUVEC), increased the activity of senescence-associated beta-galactosidase, and up-regulated the expression of aging-associated molecules such as p53, p21, and p16. Knockdown of the Notch ligand Jagged1 resulted in attenuation of Notch signaling, thereby inducing premature senescence in a way similar to knockdown of Notch1. In contrast, over-expression of Notch1 or Jagged1 extended the replicative lifespan of HUVEC and decreased the expression of aging-associated molecules. To elucidate the mechanism how inhibition of Notch signaling induces premature senescence in endothelial cells, we examined expression of various molecules by microarray analysis, and found that the expression of Id1 (inhibitor of DNA binding 1) and MKP1 (MAP kinase phosphatase 1) was significantly down-regulated by knockdown of Notch. Over-expression of Id1 improved Notch1 inhibition-induced premature senescence, which is associated with a decrease of p16 expression. Likewise, treatment with SB203580, an inhibitor of p38 MAPK, extended lifespan of Notch-deleted endothelial cells along with down-regulation of p16. These results suggest that Notch signaling and the downstream molecules (Id1 and p38) regulate endothelial cell senescence presumably via a p16-dependent pathway, and may be a new target of the therapy for age-associated vascular diseases.

Abstract 3380: Acetylation-dependent Regulation Of Notch1 Signaling In Endothelial Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Virginia Guarani ◽  
Franck Dequiedt ◽  
Andreas M Zeiher ◽  
Stefanie Dimmeler ◽  
Michael Potente
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Trichostatin A ◽  
Notch Pathway ◽  
Dependent Manner ◽  
Class Iii ◽  
Cell Fate Decisions ◽  
Knock Down

The Notch signaling pathway is a versatile regulator of cell fate decisions and plays an essential role for embryonic and postnatal vascular development. As only modest differences in Notch pathway activity suffice to determine dramatic differences in blood vessel development, this pathway is tightly regulated by a variety of molecular mechanisms. Reversible acetylation has emerged as an important post-translational modification of several non-histone proteins, which are targeted by histone deacetylases (HDACs). Here, we report that specifically the Notch1 intracellular domain (NICD) is itself an acetylated protein and that its acetylation level is tightly regulated by the SIRT1 deacetylase, which we have previously identified as a key regulator of endothelial angiogenic functions during vascular growth. Coexpression of NICD with histone acetyltransferases such as p300 or PCAF induced a dose- and time-dependent acetylation of NICD. Blocking HDAC activity using the class III HDAC inhibitor nicotinamid (NAM), but not the class I/II HDAC inhibior trichostatin A, resulted in a significant increase of NICD acetylation suggesting that NICD is targetd by class III HDACs for deacetylation. Among the class III HDACs with deacetylase activity (SIRT1, 2, 3, 5), knock down of specifically SIRT1 resulted in enhanced acetylation of NICD. Moreover, wild type SIRT1, but not a catalytically inactive mutant catalyzed the deacetylation of NICD in a nicotinamid-dependent manner. SIRT1, but SIRT2, SIRT3 or SIRT5, associated with NICD through its catalytic domain demonstrating that SIRT1 is a direct NICD deacetylase. Enhancing NICD acetylation by either overexpression of p300 or inhibition of SIRT1 activity using NAM or RNAi-mediated knock down resulted in enhanced NICD protein stability by blocking its ubiquitin-mediated degradation. Consistent with these results, loss of SIRT1 amplified Notch target gene expression in endothelial cells in response to NICD overexpression or treatment with the Notch ligand Dll4. In summary, our results identify reversible acetylation of NICD as a novel molecular mechanism to control Notch signaling and suggest that deacetylation of NICD by SIRT1 plays a key role in the dynamic regulation of Notch signaling in endothelial cells.

Pterostilbene and its nicotinate derivative ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of Sirtuin 1

2021 ◽  
Author(s):  
Lili Zhang ◽  
Jianwei Zheng ◽  
Xin Tie ◽  
Tong Lin ◽  
Wanqi Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Cardiovascular Diseases ◽  
Vascular Endothelial Cell ◽  
Cell Senescence ◽  
Sirtuin 1 ◽  
Clinical Implications ◽  
Vascular Endothelial ◽  
Resveratrol Analogues

Aim: Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study was aimed to evaluate the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. Methods and Results: All the tested compounds at the concentrations from 10-9 M to 10-6 M did not show cytotoxicity in endothelial cells. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated β-galactosidase, downregulated p21 and p53, and increased the production of NO in both angiotensin II and H2O2-induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations. Pts and Pts nicotinate did not alter Sirtuin 1 (SIRT1) expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. Conclusions: This study suggests that the Pts and Pts nicotinate ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of SIRT1. These two compounds maybe potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.

scholarly journals UNC5B Promotes Vascular Endothelial Cell Senescence via the ROS-Mediated P53 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Zhen Yang ◽  
Han Li ◽  
Pengcheng Luo ◽  
Dan Yan ◽  
Ni Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Umbilical Vein ◽  
Vascular Endothelial Cell ◽  
Cell Number ◽  
Cell Senescence ◽  
Vascular Endothelial ◽  
Vascular Disorders ◽  
P53 Pathway ◽  
Age Related

Vascular endothelial cell senescence is involved in human aging and age-related vascular disorders. Guidance receptor UNC5B is implicated in oxidative stress and angiogenesis. Nonetheless, little is known about the role of UNC5B in endothelial cell senescence. Here, we cultured primary human umbilical vein endothelial cells to young and senescent phases. Subsequently, the expression of UNC5B was identified in replicative senescent cells, and then, its effect on endothelial cell senescence was confirmed by UNC5B-overexpressing lentiviral vectors and RNA interference. Overexpression of UNC5B in young endothelial cells significantly increased senescence-associated β-galactosidase-positive cells, upregulated the mRNAs expression of the senescence-associated secretory phenotype genes, reduced total cell number, and inhibited the potential for cell proliferation. Furthermore, overexpression of UNC5B promoted the generation of intracellular reactive oxygen species (ROS) and activated the P53 pathway. Besides, overexpression of UNC5B disturbed endothelial function by inhibiting cell migration and tube formation. Nevertheless, silencing UNC5B generated conflicting outcomes. Blocking ROS production or inhibiting the function of P53 rescued endothelial cell senescence induced by UNC5B. These findings suggest that UNC5B promotes endothelial cell senescence, potentially by activating the ROS-P53 pathway. Therefore, inhibiting UNC5B might reduce endothelial cell senescence and hinder age-related vascular disorders.

scholarly journals Aberrant Activation of Notch1 Signaling in Glomerular Endothelium Induces Albuminuria

2021 ◽  
Author(s):  
Liqun Li ◽  
Qiang Liu ◽  
Tongyao Shang ◽  
Wei Song ◽  
Dongmei Xu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Notch Signaling ◽  
Molecular Mechanisms ◽  
Notch Pathway ◽  
Endothelial Glycocalyx ◽  
Notch1 Signaling ◽  
Filtration Barrier ◽  
Glomerular Endothelium

Rationale: Glomerular capillaries are lined with a highly specialized fenestrated endothelium and contribute to the glomerular filtration barrier (GFB). The Notch signaling pathway is involved in regulation of GFB, but its role in glomerular endothelium has not been investigated due to the embryonic lethality of animal models with genetic modification of Notch pathway components in the endothelium. Objective: To determine the effects of aberrant activation of the Notch signaling in glomerular endothelium and the underlying molecular mechanisms. Methods and Results: We established the ZEG-Notch1 intracellular domain (NICD1)/Tie2-tTA/Tet-O-Cre transgenic mouse model to constitutively activate Notch1 signaling in endothelial cells of adult mice. The triple transgenic mice developed severe albuminuria with significantly decreased VE-cadherin expression in the glomerular endothelium. In vitro studies showed that either NICD1 lentiviral infection or treatment with Notch ligand DLL4 markedly reduced VE-cadherin expression and increased monolayer permeability of human renal glomerular endothelial cells (HRGECs). In addition, Notch1 activation or gene knockdown of VE-cadherin reduced the glomerular endothelial glycocalyx. Further investigation demonstrated that activated Notch1 suppression of VE-cadherin was through the transcription factors SNAI1 and ERG, which bind to the -373 E-box and the -134/-118 ETS element of the VE-cadherin promoter, respectively. Conclusions: Our results reveal novel regulatory mechanisms whereby endothelial Notch1 signaling dictates the level of VE-cadherin through the transcription factors SNAI1 and ERG, leading to dysfunction of GFB and induction of albuminuria.

Alterations in Vascular Endothelial Cell-related Plasma Proteins In Thalassaemic Patients and their Correlation with Clinical Symptoms

1995 ◽  
Vol 74 (04) ◽  
pp. 1045-1049 ◽  
Author(s):  
P Butthep ◽  
A Bunyaratvej ◽  
Y Funahara ◽  
H Kitaguchi ◽  
S Fucharoen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Immunosorbent Assay ◽  
Plasma Proteins ◽  
Clinical Symptoms ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vascular Endothelial ◽  
Leg Ulcers

SummaryAn increased level of plasma thrombomodulin (TM) in α- and β- thalassaemia was demonstrated using an enzyme-linked immunosorbent assay (ELISA). Nonsplenectomized patients with β-thalassaemia/ haemoglobin E (BE) had higher levels of TM than splenectomized cases (BE-S). Patients with leg ulcers (BE-LU) were found to have the highest increase in TM level. Appearance of larger platelets in all types of thalassaemic blood was observed indicating an increase in the number of younger platelets. These data indicate that injury of vascular endothelial cells is present in thalassaemic patients.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals Vascular endothelial cell specification in health and disease

Angiogenesis ◽  
2021 ◽  
Author(s):  
Corina Marziano ◽  
Gael Genet ◽  
Karen K. Hirschi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Current Knowledge ◽  
Vascular Malformations ◽  
Immune Surveillance ◽  
Vascular Endothelial Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
The Body ◽  
Vascular Networks

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

Abstract 116: Arterial Endothelial Cell Has Stronger Angiogenic Potential Compared To Venous Endothelial Cell Through Up-regulation Of Endogenous FGF2 And FGF5 Expression In 3D Microfluidic System

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ha-Rim Seo ◽  
Hyo Eun Jeong ◽  
Hyung Joon Joo ◽  
Seung-Cheol Choi ◽  
Jong-Ho Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Assay System ◽  
Vascular Density ◽  
Angiogenic Potential ◽  
Angiogenesis Assay

Background: Human body contains many kinds of different type of endothelial cells (EC). However, cellular difference of their angiogenic potential has been hardly understood. We compared in vitro angiogenic potential between arterial EC and venous EC and investigated its underlying molecular mechanisms. Method: Used human aortic endothelial cells (HAEC) which was indicated from arterial EC and human umbilical vein endothelial cells (HUVEC) indicated from venous EC. To explore angiogenic potential in detail, we adopted a novel 3D microfluidic angiogenesis assay system, which closely mimic in vivo angiogenesis. Results: In 3D microfluidic angiogenesis assay system, HAEC demonstrated stronger angiogenic potential compared to HUVEC. HAEC maintained its profound angiogenic property under different biophysical conditions. In mRNA microarray sorted on up- regulated or down-regulated genes, HAEC demonstrated significantly higher expression of gastrulation brain homeobox 2 (GBX2), fibroblast grow factor 2 (FGF2), FGF5 and collagen 8a1. Angiogenesis-related protein assay revealed that HAEC has higher secretion of endogenous FGF2 than HUVEC. HAEC has only up-regulated FGF2 and FGF5 in this part of FGF family. Furthermore, FGF5 expression under vascular endothelial growth factor-A (VEGF-A) stimulation was higher in HAEC compared to HUVEC although VEGF-A augmented FGF5 expression in both HAEC and HUVEC. Those data suggested that FGF5 expression in both HAEC and HUVEC is partially dependent to VEGF-A stimulate. HUVEC and HAEC reduced vascular density after FGF2 and FGF5 siRNA treat. Conclusion: HAEC has stronger angiogenic potential than HUVEC through up-regulation of endogenous FGF2 and FGF5 expression

Abstract 531: Tie-2/Cre--Mediated Conditional Deletion of Lipid Phosphate Phosphatase-3 Reveals Its Role in Endothelial Cell Apoptosis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ishita Chatterjee ◽  
Kishore K Wary
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Genome Wide Association Study ◽  
Vascular Endothelial Cell ◽  
Protein Levels ◽  
Conditional Deletion ◽  
Transmission Electron ◽  
Increased Risk

Rationale: A recent genome-wide association study (GWAS) has linked a frequently occurring variation in the LPP3 (also known as PPAP2b) loci to increased risk of coronary heart disease (CAD). However, the in vivo function of LPP3 in vascular endothelial cell is incompletely understood. Goal: To address the endothelial cell (EC) specific function of Lpp3 in mice. Results: Tie-2/Cre mediated Lpp3 deletion did not affect normal vasculogenesis in early embryonic development, in contrast, in late embryonic stages it led to impaired angiogenesis associated with hemorrhage, edema and late embryonic lethal phenotype. Immunohistochemical staining followed by microscopic analyses of mutant embryos revealed reduced fibronectin and VE-cadherin expression throughout different vascular bed, and increased apoptosis in CD31+ vascular structures. Transmission electron microscopy (TEM) showed the presence of apoptotic endothelial cells and disruption of adherens junctions in mutant embryos. LPP3-knockdown in vitro showed an increase in p53 and p21 protein levels, with concomitant decrease in cell proliferation. LPP3-knockdown also decreased transendothelial electrical resistance (TER), interestingly re-expression of ß-catenin cDNA into LPP3-depleted endothelial cells partially restored the effect of loss of LPP3. Conclusion: These results suggest the ability of LPP3 to regulate survival and apoptotic activities of endothelial cells during patho/physiological angiogenesis.

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