Fluid Shear Stress Modulation of Gene Expression in Endothelial Cells

Braddock, Martin; Schwachtgen, Jean-Luc; Houston, Parul; Dickson, Marion C.; Lee, Michael J.; Campbell, Callum J.

doi:10.1152/physiologyonline.1998.13.5.241

Cited by 67 publications

(72 citation statements)

References 16 publications

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“…The strongest decrease was found for Egr-1, which is induced in the early response of ECs to shear stress (8). This response is inhibited by NO donors (10,36).…”

Section: Discussionmentioning

confidence: 96%

Nitric oxide donor induces temporal and dose-dependent reduction of gene expression in human endothelial cells

Braam¹,

Roos²,

Dijk³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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. Nitric oxide donor induces temporal and dose-dependent reduction of gene expression in human endothelial cells. Am J Physiol Heart Circ Physiol 287: H1977-H1986, 2004. First published July 8, 2004 doi:10.1152/ ajpheart.00323.2004.-The present study tested the hypothesis that acute increases in nitric oxide (NO) exert substantial influences on gene transcription in endothelial cells (ECs) via guanylyl cyclase (GC). Human umbilical veins ECs (HUVECs) were exposed to 0.1, 1, and 10 mM of sodium nitroprusside (SNP) for 4 h and to 1 mM SNP or 250 M of (Z)-1[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]-diazen-1-ium-1,2-diolate (DETA-NONOate) for 2, 4, 8, and 24 h. Also, cells were exposed to DETA-NONOate in the presence and absence of the GC inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 10 M) for 4 h. RNA was isolated, reverse transcribed, Cy3 and Cy5 labeled, and analyzed using cDNA microarrays. Increasing doses of SNP predominantly depressed gene expression in HUVECs. Gene function was related to growth, adhesion, and cell structure. DETA-NONOate evoked a wave of expression changes (maximum at 4 h), with a remarkable downregulation of the transcription factors MSX1, RELB, and Egr-1. Both SNP-and DETANONOate-induced gene expression had faded after 24 h, despite continued elevation of cGMP in the medium. Coadministration of ODQ decreased many, but not all, of the transcriptional responses to DETA-NONOate. NO pronouncedly depressed EC gene expression, in particular of transcription factors. The observation that many, but not all, transcriptional changes induced by NO could be inhibited by inhibition of GC indicates the presence of GC-independent NO actions on gene expression. Thus EC gene expression responds to NO; however, the transcriptional response fades during prolonged exposure. This could allow the EC to respond to increased shear, without vigorous changes in gene expression. microarray; nitrate tolerance; guanylate cyclase; Egr-1; V-Rel avian reticuloendotheliosis viral oncogene homolog B SUBSTANTIAL EVIDENCE is now available on the actions of nitric oxide (NO) in the vasculature (4). The, by now already classical, paradigm is that NO, released from endothelial cells (ECs) in response to shear stress, acts on vascular smooth muscle cells (VSMCs) by activating soluble guanylyl cyclase (GC), resulting in cGMP formation and vasodilation (4). In addition, NO affects multiple other processes in VSMCs, i.e., inhibits proliferation (41) and modulates expression of genes with vasoactive function (19). NO also affects EC function in an autocrine fashion and thereby inhibits adhesion, inflammation, and generation of proliferative stimuli. Indeed, exogenously applied NO can affect transcription of adhesion molecules, such as ICAM-1 and E-selectin (23) and VEGF (11) in ECs that are activated with IL-1␤ or TNF-␣. Interestingly, there is a large body of data available to support that NO actions in physiological settings are short lived, because of acute desensitization (5, 14) and slower adaptations of the GC ...

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“…The strongest decrease was found for Egr-1, which is induced in the early response of ECs to shear stress (8). This response is inhibited by NO donors (10,36).…”

Section: Discussionmentioning

confidence: 96%

Nitric oxide donor induces temporal and dose-dependent reduction of gene expression in human endothelial cells

Braam¹,

Roos²,

Dijk³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…The identification of Hath6 targets was limited to genes that are specific to endothelial cells, that might be upregulated by shear stress and that contain an E-box in their promoters. Based on the profile of shear stress-responsive genes in endothelial cells (Braddock et al, 1998;Chiu et al, 2005;Topper et al, 1996), we hypothesized that the eNOS gene is directly regulated by Hath6.…”

Section: Hath6 Is a Direct Transcriptional Regulator Of Enosmentioning

confidence: 99%

The role of Hath6, a novel shear stress-responsive transcription factor, in endothelial differentiation and function modulation

Fang¹,

Wasserman²,

Torres-Vázquez³

et al. 2014

Journal of Cell Science

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The key regulators of endothelial differentiation that is induced by shear stress are mostly unclear. Human atonal homolog 6 (Hath6 or ATOH8) is an endothelial-selective and shear-stress-responsive transcription factor. In this study, we sought to elucidate the role of Hath6 in the endothelial specification of embryonic stem cells. In a stepwise human embryonic stem cell to endothelial cell (hESC-EC) induction system, Hath6 mRNA was upregulated synchronously with endothelial determination. Subsequently, gain-of-function and lossof-function studies of Hath6 were performed using the hESC-EC induction model and endothelial cell lines. The overexpression of Hath6, which mimics shear stress treatment, resulted in an increased CD45 2 CD31 + KDR + population, a higher tubular-structure-formation capacity and increased endothelial-specific gene expression. By contrast, the knockdown of Hath6 mRNA markedly decreased endothelial differentiation. Hath6 also facilitated the maturation of endothelial cells in terms of endothelial gene expression, tubularstructure formation and cell migration. We further demonstrated that the gene encoding eNOS is a direct target of Hath6 through a reporter system assay and western blot analysis, and that the inhibition of eNOS diminishes hESC-EC differentiation. These results suggest that eNOS plays a key role in linking Hath6 to the endothelial phenotype. Further in situ hybridization studies in zebrafish and mouse embryos indicated that homologs of Hath6 are involved in vasculogenesis and angiogenesis. This study provides the first confirmation of the positive impact of Hath6 on human embryonic endothelial differentiation and function. Moreover, we present a potential signaling pathway through which shear stress stimulates endothelial differentiation.

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“…NF-BIA functions to inhibit the ubiquitous NF-B transcription factor by sequestering it in the cytoplasm and plays a significant role in inflammatory responses in low or pulsatile shear stress, for example (12,25). Glucocorticoids antagonize NF-B activity by upregulating NF-BIA expression levels (5,17).…”

Section: Discussionmentioning

confidence: 99%

Endothelial nuclear lamina is not required for glucocorticoid receptor nuclear import but does affect receptor-mediated transcription activation

Nayebosadri

2013

American Journal of Physiology-Cell Physiology

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Nayebosadri A, Ji JY. Endothelial nuclear lamina is not required for glucocorticoid receptor nuclear import but does affect receptor-mediated transcription activation. Am J Physiol Cell Physiol 305: C309 -C322, 2013. First published May 22, 2013; doi:10.1152/ajpcell.00293.2012The lamina serves to maintain the nuclear structure and stiffness while acting as a scaffold for heterochromatin and many transcriptional proteins. Its role in endothelial mechanotransduction, specifically how nuclear mechanics impact gene regulation under shear stress, is not fully understood. In this study, we successfully silenced lamin A/C in bovine aortic endothelial cells to determine its role in both glucocorticoid receptor (GR) nuclear translocation and glucocorticoid response element (GRE) transcriptional activation in response to dexamethasone and shear stress. Nuclear translocation of GR, an antiinflammatory nuclear receptor, in response to dexamethasone or shear stress (5, 10, and 25 dyn/cm 2 ) was observed via time-lapse cell imaging and quantified using a Bayesian image analysis algorithm. Transcriptional activity of the GRE promoter was assessed using a dual-luciferase reporter plasmid. We found no dependence on nuclear lamina for GR translocation from the cytoplasm into the nucleus. However, the absence of lamin A/C led to significantly increased expression of luciferase under dexamethasone and shear stress induction as well as changes in histone protein function. PCR results for NF-B inhibitor alpha (NF-BIA) and dual specificity phosphatase 1 (DUSP1) genes further supported our luciferase data with increased expression in the absence of lamin. Our results suggest that absence of lamin A/C does not hinder passage of GR into the nucleus, but nuclear lamina is important to properly regulate GRE transcription. Nuclear lamina, rather than histone deacetylase (HDAC), is a more significant mediator of shear stress-induced transcriptional activity, while dexamethasone-initiated transcription is more HDAC dependent. Our findings provide more insights into the molecular pathways involved in nuclear mechanotransduction. glucocorticoid receptor; nuclear lamina; shear stress; dexamethasone; endothelial cells CARDIOVASCULAR DISEASES SUCH as atherosclerosis are the leading cause of death in the United States. The initiation and development of atherosclerosis are typically associated with endothelial dysfunction (20,51). Endothelial cells at the lumen of blood vessels are continuously exposed to both hemodynamic shear stress and cyclic stretch due to blood flow (16). The distinct local hemodynamic profiles influence endothelial behaviors in the vasculature. Atherosclerotic lesions tend to develop at regions of disturbed flow and low shear stress at bifurcation sites and curvatures, while regions with uniform high laminar shear stress are protected (10,48,66). Endothelial responses to shear stress can be categorized as immediate [rapid release of nitric oxide (NO); (49)] as well as short-term

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Fluid Shear Stress Modulation of Gene Expression in Endothelial Cells

Cited by 67 publications

References 16 publications

Nitric oxide donor induces temporal and dose-dependent reduction of gene expression in human endothelial cells

Nitric oxide donor induces temporal and dose-dependent reduction of gene expression in human endothelial cells

The role of Hath6, a novel shear stress-responsive transcription factor, in endothelial differentiation and function modulation

Endothelial nuclear lamina is not required for glucocorticoid receptor nuclear import but does affect receptor-mediated transcription activation

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