The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model

Groenendijk, Bianca C.W.; Heiden, Kim Van der; Hierck, Beerend P.; Poelmann, Robert E.

doi:10.1152/physiol.00023.2007

Cited by 90 publications

(114 citation statements)

References 151 publications

(118 reference statements)

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“…Moreover, fluid shear stress repressed expression of ECE1, the enzyme that activates pro-endothelin by proteolitic cleavage. These two mechanisms, induction of KLF2 and repression of ECE1, indicate the attenuation of shear-induced and endothelin-1-mediated vasoconstriction, but also of shear-induced inhibition of endothelin-1-mediated proliferation (Groenendijk et al, 2007(Groenendijk et al, , 2008. Hyaluronic acid synthase-2, which is the most active enzyme for hyaluronic acid production among its family members, is markedly increased by high shear in our model.…”

Section: Discussionmentioning

confidence: 60%

Primary cilia sensitize endothelial cells for fluid shear stress

Hierck

Heiden

Alkemade

et al. 2008

Developmental Dynamics

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157

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Primary cilia are mechanosensors for fluid shear stress, and are involved in a number of syndromes and congenital anomalies. We identified endothelial cilia in areas of low shear stress in the embryonic heart. The objective of the present study was to demonstrate the role of primary cilia in mechanosensing. Ciliated embryonic endothelial cells were cultured from the heart, and non-ciliated cells from the arteries. Nonciliated cells that were subjected to fluid shear stress showed significantly less induction of the shear marker Krü ppel-Like Factor-2, as compared to ciliated cells. In addition, ciliated cells from which the cilia were chemically removed show a similar decrease in flow response. This shows that primary cilia sensitize endothelial cells for fluid shear stress. In addition, we targeted and stabilized the connection of the cilium to the cytoplasm by treatment with Colchicine and Taxol/Paclitaxel, respectively, and show that microtubular integrity is essential to sense shear stress. Developmental Dynamics 237:725-735, 2008.

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Section: Discussionmentioning

confidence: 60%

Primary cilia sensitize endothelial cells for fluid shear stress

Hierck

Heiden

Alkemade

et al. 2008

Developmental Dynamics

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157

108

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“…In line with the necessity of adequate endothelial signaling, venous clipping eventually results in a spectrum of cardiac malformations, including including atrioventricular (AV) and outflow tract (OFT) anomalies (Hogers et al, 1997(Hogers et al, , 1999. Groenendijk et al (2005) described changes in expression patterns of KLF2, endothelin-1 (ET-1), and endothelial nitric oxide synthase-3 (eNOS/NOS-3) already within 3 hr after clipping, suggestive of an increase in cardiac shear stress (Groenendijk et al, 2005(Groenendijk et al, , 2007.On a cellular level, Tgfb is a multipotent cytokine that plays pivotal roles in the regulation of proliferation, differentiation, migration, and survival of EC (Lebrin et al, 2005). After secretion and activation, Tgfb ligands bind their specific type I and type II serine/threonine kinase receptors.…”

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confidence: 99%

Tgfβ/Alk5 signaling is required for shear stress induced klf2 expression in embryonic endothelial cells

Egorova

Heiden

Pas

et al. 2011

Developmental Dynamics

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Endothelial cells (EC) translate biomechanical forces into functional and phenotypic responses that play important roles in cardiac development. Specifically, EC in areas of high shear stress, i.e., in the cardiac outflow tract and atrioventricular canal, are characterized by high expression of Krü ppel-like factor 2 (Klf2) and by transforming growth factor-beta (Tgfb)-driven endothelial-to-mesenchymal transition. Extraembryonic venous obstruction (venous clip model) results in congenital heart malformations, and venous clip-induced alterations in shear stress-related gene expression are suggestive for an increase in cardiac shear stress. Here, we study the effects of shear stress on Klf2 expression and Tgfb-associated signaling in embryonic EC in vivo using the venous clip model and in vitro by subjecting cultured EC to fluid flow. Cellular responses were assessed by analysis of Klf2, Tgfb ligands, and their downstream signaling targets. Results show that, in embryonic EC, shear stress activates Tgfb/Alk5 signaling and that induction of Klf2 is an Alk5 dependent process. Developmental Dynamics 240: [1670][1671][1672][1673][1674][1675][1676][1677][1678][1679][1680] 2011. V C 2011 Wiley-Liss, Inc.Key words: shear stress; cardiac cushions; endothelium; Klf2; Tgfb; Alk5 Accepted 14 April 2011 INTRODUCTIONBlood flow is a decisive factor guiding proper cardiovascular development and preventing vascular pathology. Biomechanical forces acting upon the vessel wall include flow-induced shear stress and pressure related cyclic stretch. Shear stress modulates endothelial structure and function and results in an accurate regulation of endothelial gene expression in vitro (Dekker et al., 2002) and in vivo (Groenendijk et al., 2004;Dekker et al., 2005). Several animal models show that congenital malformations can result from disturbed blood flow (Hogers et al., 1997;Sedmera et al., 1999;Tobita et al., 2002;Hove et al., 2003;Dealmeida et al., 2007;Butcher et al., 2007). The large and rapid changes in volume and geometry of cardiac compartments during development are translated into local changes in shear stress and concomitant gene expression patterns of, e.g., Krü ppel like factor 2 (KLF2) (Groenendijk et al., 2004).KLF2 is a shear responsive transcription factor essential in establishing and maintaining endothelial function by regulating the expression of many genes (Dekker et al., 2002(Dekker et al., , 2006SenBanerjee et al., 2004;Boon and Horrevoets, 2009). Exposure of adult endothelium to high and pulsatile shear stress causes an increase in KLF2 expression (Dekker et al., 2002;Wang et al., 2006), which induces a quiescent and atheroprotective phenotype, in part through inhibition of transforming growth factor-beta (TGFb) signaling (Boon et al., 2007). The increase of KLF2 protein levels under shear stress is mediated by two mechanisms, i.e., activation of the KLF2 promoter and stabilization of KLF2 mRNA (Dekker et al., 2002;van Thienen et al., 2006). Myocyte enhancer binding factor 2C (Mef2C) is one of the transcriptiona...

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“…Our qPCR assay indicated that SAHA could increase KLF2 mRNA expression at 10 μmol/L (Figure 1C). Meanwhile, SAHA (10 μmol/L) also significantly decreased the mRNA expression of known KLF2‐target gene endothelin‐128, 29 (Figure S2). Taken together, our data suggest that SAHA is a bona‐fide KLF2 activator.…”

Section: Resultsmentioning

confidence: 95%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model

Cited by 90 publications

References 151 publications

Primary cilia sensitize endothelial cells for fluid shear stress

Primary cilia sensitize endothelial cells for fluid shear stress

Tgfβ/Alk5 signaling is required for shear stress induced klf2 expression in embryonic endothelial cells

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

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