Differential regulation of the von Willebrand factor and Flt-1 promoters in the endothelium of hypoxanthine phosphoribosyltransferase–targeted mice

Minami, Takashi; Donovan, Diana; Tsai, Jo C.; Rosenberg, Robert D.; Aird, William C.

doi:10.1182/blood-2002-03-0955

Cited by 32 publications

(36 citation statements)

References 39 publications

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“…3), mechanisms independent of the chemokine might be involved. [31][32][33] LSEC enhanced the CXCL12-driven transmigration of all CD4 ϩ T cell subsets investigated and the CXCL9-dependent transmigration of cytokine-producing memory cells, whereas the chemotactic effects of CXCL16, CCL20, and CCL21 on CD4 ϩ T cells were not significantly altered under the given experimental conditions. Thus, LSEC seem to exert differential effects on certain chemokines.…”

Section: Discussionmentioning

confidence: 92%

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

et al. 2008

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Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells ( H omeostatic extravasation into the liver parenchyma and transmigration of T cells into sites of inflammation under pathological conditions such as hepatitis and cholangitis are mediated by multiple steps involving activation and firm adhesion followed by egress. The process is closely regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the cell surface. 1,2 Within the liver, lymphocyte adhesion, a prerequisite for transmigration, occurs mainly within the sinusoidal circulation. Thus, T cell immigration into the liver is presumed to happen predominantly via the sinusoids. 3 Liver sinusoidal endothelial cells (LSEC) lining the sinusoids form a morphologically and functionally distinct endothelium that lacks a basement membrane, fails to form tight junctions, and displays fenestrae grouped to sieve plates. 4 In contrast to other tissues, selectins are not necessary for the initial adhesion of leukocytes to the liver microvasculature. The

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Section: Discussionmentioning

confidence: 92%

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

et al. 2008

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“…1 Subsequently, we reported that a 1-kb fragment of the human VEGFR1 promoter (between Ϫ748 and ϩ284) contains information for endothelial-restricted expression in transgenic mice. 2 In the latter study, a single copy of the VEGFR1 promoter was targeted to the Hprt locus, thus providing a means to control for the effects of copy number and integration site on expression. In the current study, we used an identical Hprt targeting strategy to evaluate the activity of the VEGFR1 promoter containing a point mutation of 1 of the 2 ETS motifs, the CRE site, or the EGR binding element.…”

Section: Introductionmentioning

confidence: 99%

Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo

Jin

Liu

Suehiro

et al. 2009

Blood

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Vascular endothelial growth factor receptor 1 (VEGFR1) is a marker for endothelialspecific gene expression. We previously reported that the human VEGFR1 promoter (between ؊748 and ؉284) contains information for expression in the intact endothelium of transgenic mice. The objective of this study was to dissect the cis-regulatory elements underlying VEGFR1 promoter activity in vitro and in vivo. In primary endothelial cells, binding sites for E74-like factor 1 (ELF-1; between ؊49 and ؊52), cyclic adenosine monophosphate response element binding (CREB; between ؊74 and ؊81), and early growth response factor 1/3 (EGR-1/3; between ؊16 to ؊25) were shown to play a positive role in gene transcription, whereas a putative E26 transformation-specific sequence (ETS) motif between ؊36 and ؊39 had a net negative effect on promoter activity.

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“…eNOS is comparable in its cell specificity with common endothelial markers such as CD31/PECAM and von Willebrand factor. mRNAs known to be even more restricted to the vascular endothelium than eNOS are uncommon but include the endothelial growth factor receptor tyrosine kinases VEGF-R1 (Flt-1), VEGF-R2 (Flk-1/KDR), Tie-1, and Tie2/Tek (8). Elucidating the mechanisms involved in the endothelial cell-specific eNOS would provide valuable insight into the poorly understood basis for endothelium-specific gene regulation.…”

mentioning

confidence: 99%

The Cell-specific Expression of Endothelial Nitric-oxide Synthase

Chan

Fish

D'Abreo

et al. 2004

Journal of Biological Chemistry

227

234

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The basis for the endothelial cell-restricted expression of endothelial nitric-oxide synthase (eNOS) is not known. While transgenic promoter/reporter mice demonstrated endothelium cell-specific eNOS expression, we found robust expression of episomal eNOS promoter/reporter constructs in cell types that do not express the native eNOS transcript. To explore the mechanism underlying this differential activity pattern of chromatin-versus episomebased eNOS promoters, we examined the methylation status of 5-regulatory sequences of the human eNOS gene. DNA methylation differed dramatically between endothelial and nonendothelial cell types, including vascular smooth muscle cells. This same cell type-specific methylation pattern was observed in vivo in endothelial and vascular smooth muscle cells of the mouse aorta at the native murine eNOS promoter. We addressed the functional consequences of methylation on eNOS transcription using transient transfection of in vitro methylated promoter/reporter constructs and found that methylated constructs exhibited a marked decrease in the synergistic action of Sp1, Sp3, and Ets1 on eNOS promoter activity. The addition of methyl-CpG-binding protein 2 further reduced the transcriptional activity of methylated eNOS constructs. Importantly, chromatin immunoprecipitation demonstrated the presence of Sp1, Sp3, and Ets1 at the native eNOS promoter in endothelial cells but not in vascular smooth muscle cells. Finally, robust expression of eNOS mRNA was induced in nonendothelial cell types following inhibition of DNA methyltransferase activity with 5-azacytidine, demonstrating the importance of DNA methylation-mediated repression. This report is the first to show that promoter DNA methylation plays an important role in the cell-specific expression of a constitutively expressed gene in the vascular endothelium.

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Differential regulation of the von Willebrand factor and Flt-1 promoters in the endothelium of hypoxanthine phosphoribosyltransferase–targeted mice

Cited by 32 publications

References 39 publications

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo

The Cell-specific Expression of Endothelial Nitric-oxide Synthase

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