Repressors NFI and NFY Participate in Organ-Specific Regulation of von Willebrand Factor Promoter Activity in Transgenic Mice

Nassiri, Marjan; Liu, Ju; Kulak, Stephen C.; Uwiera, Richard R. E.; Aird, William C.; Ballermann, Barbara J.; Jahroudi, Nadia

doi:10.1161/atvbaha.110.206680

Cited by 24 publications

(21 citation statements)

References 23 publications

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“…This VWF mosaicism may be static (aorta) or dynamically regulated by transcriptional mechanisms involving the VWF promoter . For example, VWF is virtually undetectable within resting glomerular capillaries of mice but is inducible by inhibition of the repressor nuclear factor‐I . A patchy staining for VWF has been also reported in normal human kidney tissue and, in vitro, with primary glomerular EC (GEC) …”

Section: Are All Endothelial Cells Made Equal?mentioning

confidence: 99%

Endothelial cells: source, barrier, and target of defensive mediators

Roumenina

Rayes

Frimat

et al. 2016

Immunological Reviews

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Endothelium is strategically located at the interface between blood and interstitial tissues, placing thus endothelial cell as a key player in vascular homeostasis. Endothelial cells are in a dynamic equilibrium with their environment and constitute concomitantly a source, a barrier, and a target of defensive mediators. This review will discuss the recent advances in our understanding of the complex crosstalk between the endothelium, the complement system and the hemostasis in health and in disease. The first part will provide a general introduction on endothelial cells heterogeneity and on the physiologic role of the complement and hemostatic systems. The second part will analyze the interplay between complement, hemostasis and endothelial cells in physiological conditions and their alterations in diseases. Particular focus will be made on the prototypes of thrombotic microangiopathic disorders, resulting from complement or hemostasis dysregulation-mediated endothelial damage: atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Novel aspects of the pathophysiology of the thrombotic microangiopathies will be discussed.

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Section: Are All Endothelial Cells Made Equal?mentioning

confidence: 99%

Endothelial cells: source, barrier, and target of defensive mediators

Roumenina

Rayes

Frimat

et al. 2016

Immunological Reviews

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“…VWF promoter activity is highly influenced by the interaction of a number of transacting factors that function as activators, repressors, or have a dual function (Fig. A) . To determine whether alterations observed in gene array analyses are also reflected by other gene expression analyses methods, we explored the expression pattern of the previously identified VWF regulatory transacting factors by RT‐PCR analyses (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…in vivo analyses of the VWF promoter demonstrated that while the sequence −487 to +247 exhibited endothelial specificity, it was only sufficient for promoter activation in the brain , and additional regions were required for activation in other organs . Furthermore, in vivo mutational analyses of the VWF promoter transgene demonstrated that mutation in the NFI binding site leads to VWF promoter sequence −487 to +247‐driven gene expression in endothelial cells of lung and heart, whereas mutations in the repressor NFY binding site (+226 to +234) results in VWF promoter activation in kidney endothelial cells . These results demonstrate a clear role for the repressors NFI and NFY in organ‐specific regulation of the VWF promoter.…”

Section: Introductionmentioning

confidence: 88%

“…Chromatin immunoprecipitations (ChIP) were performed using antibodies against target transacting factors, acetylated histones, and primers that amplified target VWF promoter sequences, as previously described . The two potential methylation sites (cytosines in CpG dinucleotide) located in the endothelial‐specific VWF promoter (−422 and +119) were tested for methylation using OneStep qMethyl kit (Zymo Research, Irvine, CA), according to company's manual.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally VWF expression is modulated in response to external stimuli such as shear stress, mechanical stress, hypernatremia, irradiation, and hypoxia; and vascular bed‐specific heterogeneity in response to some stimuli such as hypoxia were also observed . Vascular‐bed heterogeneity of VWF expression has been studied in vivo using several wild‐type and genetically modified mouse models . However, endothelial cell‐specificity of VWF expression has been mainly explored in vitro, using cultured endothelial cells compared with cells of nonendothelial origin.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of von Willebrand Factor Gene in Endothelial Cells That Are Programmed to Pluripotency and Differentiated Back to Endothelial Cells

et al. 2019

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Endothelial cells play a central role in physiological function and pathophysiology of blood vessels in health and disease. However, the molecular mechanism that establishes the endothelial phenotype, and contributes to its signature cell type-specific gene expression, is not yet understood. We studied the regulation of a highly endothelial-specific gene, von Willebrand factor (VWF), in induced pluripotent stem cells generated from primary endothelial cells (human umbilical vein endothelial cells [HUVEC] into a pluripotent state [HiPS]) and subsequently differentiated back into endothelial cells. This allowed us to explore how VWF expression is regulated when the endothelial phenotype is revoked (endothelial cells to HiPS), and re-established (HiPS back to endothelial cells [EC-Diff]). HiPS were generated from HUVECs, their pluripotency established, and then differentiated back to endothelial cells. We established phenotypic characteristics and robust angiogenic function of EC-Diff. Gene array analyses, VWF chromatin modifications, and transacting factors binding assays were performed on the three cell types (HUVEC, HiPS, and EC-Diff). The results demonstrated that generally cohorts of transacting factors that function as transcriptional activators, and those that contribute to histone acetylation and DNA demethylation, were significantly decreased in HiPS compared with HUVECs and EC-Diff. In contrast, there were significant increases in the gene expression levels of epigenetic modifiers that function as methyl transferases in HiPS compared with endothelial cells. The results demonstrated that alterations in chromatin modifications of the VWF gene, in addition to expression and binding of transacting factors that specifically function as activators, are responsible for establishing endothelial specific regulation of the VWF gene. STEM CELLS 2019;37:542-554 SIGNIFICANCE STATEMENTIn these studies, a novel approach involving generation and differentiation of induced pluripotent stem cells is used to revoke and subsequently re-establish a specific cell phenotype, namely endothelial cells, to explore transcriptional regulatory networks that are associated with establishing cell type specific gene regulation. It provides a novel approach, compared with classic analyses of differential gene regulation among cells of distinct phenotypes, toward determining how cell type specific gene expression is regulated. The process allows for determining simultaneously what the critical components that contribute to silencing are, as well as activating target cell-type specific gene regulation.

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Plasma levels of von Willebrand factor in type 2 diabetes patients with and without cardiovascular diseases: A meta‐analysis

Peng

Wang

Fan

et al. 2019

Diabetes Metabolism Res

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SummaryChronic vascular complications are the major causes of death and disability of type 2 diabetes mellitus (T2DM) patients. von Willebrand factor (vWF) is involved in pathogenesis of cardiovascular diseases (CVD). Previous studies showed elevated plasma levels of vWF in T2DM patients with CVD, but the association has not been validated. The aim of this meta‐analysis was to compare plasma levels of vWF in T2DM patients with and without CVD. We performed a meta‐analysis based on published case‐control studies of vWF in T2DM patients with and without CVD indexed in PubMed and other databases updated to April 2018. After independently assessing methodological quality and extracting data, 9 eligible studies were obtained including 576 cases and 632 controls. The standard mean difference (SMD) and 95% confidence intervals (95% CI) were calculated using random‐effects model. Meta‐analysis showed that plasma level of vWF was significantly higher in T2DM patients with CVD than T2DM patients without CVD (SMD = 0.61; 95% CI, 0.32‐0.90; P < .00001). Subgroup and sensitivity analyses confirmed the robustness of the results. Plasma levels of vWF are significantly elevated in patients with T2DM complicated by CVD. This study helps further characterize the prognostic value of vWF for cardiovascular complications in T2DM patients.

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Repressors NFI and NFY Participate in Organ-Specific Regulation of von Willebrand Factor Promoter Activity in Transgenic Mice

Cited by 24 publications

References 23 publications

Endothelial cells: source, barrier, and target of defensive mediators

Endothelial cells: source, barrier, and target of defensive mediators

Regulation of von Willebrand Factor Gene in Endothelial Cells That Are Programmed to Pluripotency and Differentiated Back to Endothelial Cells

Plasma levels of von Willebrand factor in type 2 diabetes patients with and without cardiovascular diseases: A meta‐analysis

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