Primary cilia sensitize endothelial cells for fluid shear stress

Hierck, Beerend P.; Heiden, Kim Van der; Alkemade, Fanneke E.; Pas, Simone van de; Thienen, J.V. van; Groenendijk, Bianca C.W.; Bax, Wilhelmina H.; Laarse, Arnoud van der; DeRuiter, Marco C.; Horrevoets, Anton J.G.; Poelmann, Robert E.

doi:10.1002/dvdy.21472

Cited by 159 publications

(115 citation statements)

References 72 publications

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“…5). KLF2 was induced in CEC by a factor 2.5 (comparable to the previously reported values in these EC; Hierck et al, 2008) and 2.3 under shear stress and Tgfb stimulation, respectively. Induction by both stimuli was attenuated in the presence of the Alk5 kinase inhibitor.…”

Section: Klf2 Induction Is Alk5 Kinase Dependent In Embryonic Ec But supporting

confidence: 87%

“…Different shear conditions result in specific endothelial cell responses (Garcia-Cardena et al, 2001;Wasserman and Topper, 2004;Groenendijk et al, 2007) and the rapidly changing geometry and hemodynamics of the developing cardiovascular system necessitates the accurate response of shear stress-dependent intracellular mechanisms. Primary cilia have been described to play a critical role in the process of mechanosensing by modulating endothelial responses to shear stress (Nauli et al, 2008;Poelmann et al, 2008;Hierck et al, 2008). We have recently demonstrated the central role of primary cilia in rendering EC prone to enhanced shearinduced activation of Tgfb/Alk5 signaling and EndoMT in vitro and in vivo (Egorova et al, 2011).…”

Section: Discussionmentioning

confidence: 90%

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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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Section: Klf2 Induction Is Alk5 Kinase Dependent In Embryonic Ec But supporting

confidence: 87%

Section: Discussionmentioning

confidence: 90%

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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“…Primary cilia have two well-defined, independent functions: facilitating Hedgehog (Hh) signaling and detecting lowmagnitude shear stress (Anderson, 2006;Egorova et al, 2012;Goetz et al, 2014;Hierck et al, 2008;Roy, 2012;Van der Heiden et al, 2011;Wilson and Stainier, 2010). To determine whether Hh signaling is necessary for endocardial Notch activation, we treated Tg(Tp1:VenusPest); Tg(myl7:dsRed) Notch reporter embryos with cyclopamine to antagonize Hh signaling downstream of primary cilia (Chen et al, 2002;Stanton and Peng, 2010).…”

Section: Primary Cilia Are Required For Notch Activation In Endocardimentioning

confidence: 99%

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

et al. 2015

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Congenital heart disease often features structural abnormalities that emerge during development. Accumulating evidence indicates a crucial role for cardiac contraction and the resulting fluid forces in shaping the heart, yet the molecular basis of this function is largely unknown. Using the zebrafish as a model of early heart development, we investigated the role of cardiac contraction in chamber maturation, focusing on the formation of muscular protrusions called trabeculae. By genetic and pharmacological ablation of cardiac contraction, we showed that cardiac contraction is required for trabeculation through its role in regulating notch1b transcription in the ventricular endocardium. We also showed that Notch1 activation induces expression of ephrin b2a (efnb2a) and neuregulin 1 (nrg1) in the endocardium to promote trabeculation and that forced Notch activation in the absence of cardiac contraction rescues efnb2a and nrg1 expression. Using in vitro and in vivo systems, we showed that primary cilia are important mediators of fluid flow to stimulate Notch expression. Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation.

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“…113,114 Recent studies provide evidence that the primary cilia mediate the mechanism by which ECs sense and respond to shear stress. 115 Because primary cilia are physically connected to cytoskeletal microtubules, their bending by flow is assumed to transmit shear stress signals into the cells through the cytoskeleton. The bending of the primary cilia may also activate Ca 2+ -permeable ion channels and trigger Ca 2+ signaling.…”

Section: Primary Ciliamentioning

confidence: 99%

Vascular Mechanobiology Endothelial Cell Responses to Fluid Shear Stress

Ando

Yamamoto

2009

Circ J

321

138

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lood vessels are not just tubes through which the blood passes, but are active organs with a variety of functions that maintain the homeostasis of the circulatory system. It is a well-established fact that vascular functions are controlled by biochemical mediators, including hormones, cytokines, and neurotransmitters. However, it has recently become apparent that the biomechanical forces generated by blood flow and blood pressure regulate vascular functions. Flowing blood constantly exerts a frictional force, shear stress, on the endothelial cells (ECs) lining blood vessel walls, and the ECs respond to shear stress by changing their morphology, function, and gene expression. EC responses to shear stress are thought to play a critical role in blood-flow-dependent phenomena, including angiogenesis, 1 vascular remodeling, 2 and atherosclerosis. 3 The fact that ECs respond to shear stress indicates that they have the ability to sense shear stress as a signal and transmit it into the interior of the cell. Numerous studies have been devoted to clarifying the mechanisms of shear stress mechanotransduction, and they have demonstrated that multiple signal transduction pathways are activated by shear stress through a variety of membrane molecules and cellular microdomains, including ion channels, G protein, tyrosine kinase receptors, adhesive proteins, caveolae, the cytoskeleton, the glycocalyx, and primary cilia. The mechanisms of shear stress mechanotransduction, however, are not yet fully understood. We review the literature on EC responses to shear stress and the role of their responses in the regulation of the circulatory system, and address the issues of shear stress sensing and signaling mechanisms. EC Responses to Shear StressA considerable amount of information on EC responses to shear stress has accumulated as a result of various in vivo, ex vivo, and in vitro experiments. In vitro experiments in which cultured ECs have been subjected to controlled levels of shear stress in fluid-dynamically designed flow-loading devices, in particular, have enabled analysis of EC responses to shear stress at cellular and molecular levels. [4][5][6][7] In this section, we describe the effects of shear stress on EC morphology, function, and gene expression, and on the differentiation of immature cells, such as endothelial progenitor cells (EPCs) and embryonic stem (ES) cells, into ECs. MorphologyWhen examined in vivo, ECs lining segments of blood vessels in which blood flow is rapid and unidirectional are spindle-shaped and aligned with their long axis parallel to the direction of blood flow, whereas ECs lining segments in which blood flow is turbulent or stagnant are much rounder in shape and do not have a uniform orientation. 8,9 Because of these findings, shear stress is thought to determine the shape and orientation of ECs. When cultured ECs have been J 2009; 73: 1983 -1992)

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Primary cilia sensitize endothelial cells for fluid shear stress

Cited by 159 publications

References 72 publications

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

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

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

Vascular Mechanobiology Endothelial Cell Responses to Fluid Shear Stress

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