Deciphering the Endothelial Shear Stress Sensor

Poelmann, Robert E.; Heiden, Kim Van der; Groot, Adriana Gittenberger-de; Hierck, Beerend P.

doi:10.1161/circulationaha.107.753889

Cited by 44 publications

(27 citation statements)

References 22 publications

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“…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%

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: 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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“…PKD1 and PKD2 have been shown to participate in flowdependent calcium release in endothelial cells, kidney epithelial cells and in the LR organizer. Importantly, the PKD1-PKD2 complex seems specifically involved in fluid flow and not in mechanical load sensing in endothelial cell culture (Nauli et al, 2008;Poelmann et al, 2008;AbouAlaiwi et al, 2009). Primary cilia are, however, fragile structures that can break when subject to sufficiently strong flow-induced shear stress (Nauli et al, 2008).…”

Section: Low-speed Flow Sensing Through Primary Ciliamentioning

confidence: 99%

“…This mechanism ensures that embryonic endothelial cells sense a narrow flow velocity range. It is noteworthy that only 25% of endothelial cells are ciliated, leaving many wide areas nonciliated in the chicken embryonic heart (Poelmann et al, 2008). Nevertheless, non-ciliated cells seem connected to neighboring ciliated cells through intercellular calcium exchange (Nauli et al, 2008).…”

Section: Low-speed Flow Sensing Through Primary Ciliamentioning

confidence: 99%

Fluid flows and forces in development: functions, features and biophysical principles

et al. 2012

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Throughout morphogenesis, cells experience intracellular tensile and contractile forces on microscopic scales. Cells also experience extracellular forces, such as static forces mediated by the extracellular matrix and forces resulting from microscopic fluid flow. Although the biological ramifications of static forces have received much attention, little is known about the roles of fluid flows and forces during embryogenesis. Here, we focus on the microfluidic forces generated by cilia-driven fluid flow and heart-driven hemodynamics, as well as on the signaling pathways involved in flow sensing. We discuss recent studies that describe the functions and the biomechanical features of these fluid flows. These insights suggest that biological flow determines many aspects of cell behavior and identity through a specific set of physical stimuli and signaling pathways.

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“…The biochemical mechanisms that enable endothelial cells to detect flow patterns are beginning to be understood (15)(16)(17). Arterial endothelial cells possess a single cilium able to detect the mechanical forces of blood flow (18)(19)(20) that distinguish disturbed flow from laminar flow. This in turn dictates endothelial cell phenotype.…”

Section: Inflammation Of the Vessel Wallmentioning

confidence: 99%

Emerging role of Toll-like receptors in atherosclerosis

Curtiss

Tobias

2009

Journal of Lipid Research

199

146

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Atherosclerosis is inflammation of the vessel wall of the arterial tree. This inflammation arises at specific areas that experience disturbed blood flow such as bifurcations and the lesser curvature of the aortic arch. Although all endothelial cells are exposed to comparable levels of circulating plasma cholesterol, only endothelial cells overlaying lesions display an inflamed phenotype. This occurs even in the absence of any additional exacerbating disease factors because blood flow controls the expression of Toll-like receptors (TLR), which are initiators of cellular activation and inflammation. TLR2-and 4-expression exert an overall proatherogenic effect in hyperlipidemic mice. TLR activation of the endothelium promotes lipid accumulation and leukocyte accumulation within lesions.-Curtiss, L. K., and P. S. Tobias. Emerging role of Toll-like receptors in atherosclerosis. J. Lipid Res. 2009. 50: S340-S345.

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Deciphering the Endothelial Shear Stress Sensor

Cited by 44 publications

References 22 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

Fluid flows and forces in development: functions, features and biophysical principles

Emerging role of Toll-like receptors in atherosclerosis

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