Reversing Blood Flows Act through klf2a to Ensure Normal Valvulogenesis in the Developing Heart

Vermot, Julien; Forouhar, Arian S.; Liebling, Michael; Wu, David; Plummer, Diane; Gharib, Morteza; Fraser, Scott E.

doi:10.1371/journal.pbio.1000246

Cited by 283 publications

(496 citation statements)

References 52 publications

(86 reference statements)

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“…Our study shows that degradation of KLF2 by FBW7 is indispensable for angiogenesis in mice. Moreover, Klf2 is essential for normal valve development [56] and flow-induced angiogenesis during aortic arch development by regulating the expression of miR126 in zebrafish [12]. Our data showed that zebrafish Klf2 is also a target of zebrafish Fbw7.…”

Section: Discussionmentioning

confidence: 63%

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Wang

Liu

et al. 2013

Cell Res

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F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCF FBW7 (a complex of SKP1, cullin-1 and FBW7), plays important roles in various physiological and pathological processes. Although FBW7 is required for vascular development, its function in the endothelium remains to be investigated. In this study, we show that FBW7 is an important regulator of endothelial functions, including angiogenesis, leukocyte adhesion and the endothelial barrier integrity. Using RNA interference, we found that the depletion of FBW7 markedly impairs angiogenesis in vitro and in vivo. We identified the zinc finger transcription factor Krüppel-like factor 2 (KLF2) as a physiological target of FBW7 in endothelial cells. Knockdown of FBW7 expression resulted in the accumulation of endogenous KLF2 protein in endothelial cells. FBW7-mediated KLF2 destruction was shown to depend on the phosphorylation of KLF2 via glycogen synthase kinase-3 (GSK3) at two conserved phosphodegrons. Mutating these phosphodegron motifs abolished the FBW7-mediated degradation and ubiquitination of KLF2. The siRNAmediated knockdown of FBW7 showed that KLF2 is an essential target of FBW7 in the regulation of endothelial functions. Moreover, FBW7-mediated KLF2 degradation was shown to be critical for angiogenesis in teratomas and in zebrafish development. Taken together, our study suggests a role for FBW7 in the processes of endothelial cell migration, angiogenesis, inflammation and barrier integrity, and provides novel insights into the regulation of KLF2 stability in vivo.

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Section: Discussionmentioning

confidence: 63%

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Wang

Liu

et al. 2013

Cell Res

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“…Additionally, backflow may decrease with advanced developmental stage because of differences in myocardial contractility between HH13 and HH18 (figure 8). While it is critical for adult heart valves to prevent intracardiac retrograde blood flow, studies in the embryonic zebrafish heart suggest that shear stimulus produced by backflow in the developing heart is required for normal valvulogenesis [56]. Our results may therefore reflect a transition in cardiac pumping that is likely essential for proper heart development.…”

Section: Discussionmentioning

confidence: 73%

Blood flow through the embryonic heart outflow tract during cardiac looping in HH13–HH18 chicken embryos

Midgett

Chivukula

Dorn

et al. 2015

J. R. Soc. Interface.

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Blood flow is inherently linked to embryonic cardiac development, as haemodynamic forces exerted by flow stimulate mechanotransduction mechanisms that modulate cardiac growth and remodelling. This study evaluated blood flow in the embryonic heart outflow tract (OFT) during normal development at each stage between HH13 and HH18 in chicken embryos, in order to characterize changes in haemodynamic conditions during critical cardiac looping transformations. Two-dimensional optical coherence tomography was used to simultaneously acquire both structural and Doppler flow images, in order to extract blood flow velocity and structural information and estimate haemodynamic measures. From HH13 to HH18, peak blood flow rate increased by 2.4-fold and stroke volume increased by 2.1-fold. Wall shear rate (WSR) and lumen diameter data suggest that changes in blood flow during HH13-HH18 may induce a shear-mediated vasodilation response in the OFT. Embryo-specific four-dimensional computational fluid dynamics modelling at HH13 and HH18 complemented experimental observations and indicated heterogeneous WSR distributions over the OFT. Characterizing changes in haemodynamics during cardiac looping will help us better understand the way normal blood flow impacts proper cardiac development.

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“…Normal blood flow is essential for multiple facets of cardiac development (Bartman and Hove, 2005), including the formation of AV endocardial cushions (Hove et al, 2003;Vermot et al, 2009), the enlargement and elongation of outer curvature cardiomyocytes (Auman et al, 2007), and the maturation of the conduction system (Sedmera et al, 2005;Chi et al, 2008). These processes, like trabeculation, take place after cardiac function begins and, therefore, occur in the presence of the biomechanical impact of blood flow.…”

Section: Normal Blood Flow Is Required For the Progression Of Trabecumentioning

confidence: 99%

“…The shear forces generated by circulating blood are known to have a significant impact on heart development (Hove et al, 2003;Vermot et al, 2009;Culver and Dickinson, 2010), and the exposure of the endocardium to shear forces could alter its signaling to the myocardium. Notably, it is not yet known whether alteration of hemodynamics can affect Neuregulin signal transduction between the endocardium and myocardium (Lai et al, 2010).…”

Section: Developmental Dynamicsmentioning

confidence: 99%

Dependence of cardiac trabeculation on neuregulin signaling and blood flow in zebrafish

Peshkovsky

Totong

Yelon

2011

Developmental Dynamics

121

160

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Maturation of the developing heart requires the structural elaboration of the embryonic ventricle through the process of trabeculation. Trabeculae form as the ventricular myocardium protrudes into the lumen of the chamber, thereby increasing muscle mass and altering functional output. Little is understood about the cellular basis for trabeculation and its genetic regulation. Here, we establish the utility of the zebrafish embryo for the analysis of the mechanisms driving trabeculation. In zebrafish, we can follow trabeculation in four dimensions and define morphologically discrete stages for the initiation, propagation, and network elaboration that form the ventricular trabeculae. We find that Neuregulin/ErbB signaling is required for the initial protrusion of the myocardium into the ventricular lumen. Additionally, we demonstrate that optimal blood flow through the ventricle is important for the advancement of trabeculation. Thus, our results indicate that the zebrafish provides a valuable model for investigating possible causes of congenital defects in trabeculation. Developmental Dynamics 240:446-456,

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Reversing Blood Flows Act through klf2a to Ensure Normal Valvulogenesis in the Developing Heart

Abstract: The directionality of local blood flow in the zebrafish embryonic heart is essential for proper heart valve formation.

Cited by 283 publications

References 52 publications

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Blood flow through the embryonic heart outflow tract during cardiac looping in HH13–HH18 chicken embryos

Dependence of cardiac trabeculation on neuregulin signaling and blood flow in zebrafish

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