RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node

Vicente‐Steijn, Rebecca; Kelder, Tim P.; Tertoolen, Leon G.J.; Wisse, Lambertus J.; Pijnappels, Daniël A.; Poelmann, Robert E.; Schalij, Martin J.; DeRuiter, Marco C.; Groot, Adriana C. Gittenberger‐de; Jongbloed, Monique R.M.

doi:10.1093/cvr/cvx104

Cited by 19 publications

(25 citation statements)

References 45 publications

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“…In control embryos the AVN region was devoid of ISL1, while it could be detected in this region in the ROCK inhibited embryos. In the SV‐AVC continuity in controls ISL1 expression is present as described earlier (Vicente‐Steijn et al, ). After ROCK inhibition, however, in which the SV‐AVC continuity was diminished to almost absent (Fig.…”

Section: Resultsmentioning

confidence: 67%

“…Understanding the developmental processes ultimately resulting in a mature, cellular heterogeneous AVN is crucial to understand arrhythmias and conduction disturbances arising from this structure. Previously we have described the effect of RHOA‐ROCK signaling on the function and development of the SAN (Vicente‐Steijn et al ) in chicken embryos, showing that it is essential for lateralization and differentiation of the SAN. ROCK inhibition resulted in immaturity of the SAN exemplified by upregulation of ISL1 expression.…”

Section: Discussionmentioning

confidence: 92%

“…After ROCK inhibition, however, in which the SV‐AVC continuity was diminished to almost absent (Fig. G–R), ISL1 upregulation (Vicente‐Steijn et al, ) could not be evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Recordings were conducted in control (n = 29) and ROCK inhibited (n = 20) hearts (HH28–31) as described previously (Kolditz et al, ; Vicente‐Steijn et al, ; Kelder et al, ; Vicente‐Steijn et al, ). Hearts were placed in a temperature‐controlled (37 ± 0.1 °C) superperfused (oxygenated Tyrode) tissue bath and allowed to equilibrate for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…In follow up of our study on the role of RHOA–ROCK signaling on the SAN (Vicente‐Steijn et al ) we aimed in the current study to first generate a novel model system to investigate AV conduction disturbances during development by in ovo inhibition of the RHOA‐ROCK signaling pathway. Because RHOA is involved in cellular migration, it was hypothesized that AV block after RHOA inhibition may relate to a diminished or maldeveloped myocardial connection between the sinus venosus and the atrioventricular (AV) canal (further referred to as SV‐AVC continuity).…”

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confidence: 99%

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Disruption of RHOA‐ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node

Kelder

Vicente‐Steijn

Poelmann

et al. 2018

The Anatomical Record

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The RHOA‐ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. The current study aims to detect functional AVN disorders after disturbing RHOA‐ROCK signaling in chicken embryos. RHOA‐ROCK signaling was inhibited chemically by using the Rho‐kinase inhibitor compound Y‐27632 in avian embryos (20 experimental and 29 control embryos). Morphological examination of control embryos show a myocardial sinus venosus to atrioventricular canal continuity, contributing to the transitional zone of the AVN. ROCK inhibited embryos revealed lateralization and diminished myocardial sinus venosus to atrioventricular canal continuity and at the severe end of the phenotype hypoplasia of the AVN region. Ex ovo micro‐electrode recordings showed an AV conduction delay in all treated embryos as well as cases with first, second (Wenkebach and Mobitz type) and third‐degree AV block which could be explained by the spectrum of severity of the morphological phenotype. Laser capture microdissection and subsequent qPCR of tissue collected from this region revealed disturbed expression of HCN1, ISL1, and SHOX2. We conclude that RHOA‐ROCK signaling is essential for normal morphological development of the myocardial continuity between the sinus venosus and AVN, contributing to the transitional zone, and possibly the compact AVN region. Disturbing the RHOA‐ROCK signaling pathway results in AV conduction disturbances including AV block. The RHOA‐ROCK inhibition model can be used to further study the pathophysiology and therapeutic strategies for AV block. Anat Rec, 302:83–92, 2019. © 2018 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 92%

“…After ROCK inhibition, however, in which the SV‐AVC continuity was diminished to almost absent (Fig. G–R), ISL1 upregulation (Vicente‐Steijn et al, ) could not be evaluated.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Disruption of RHOA‐ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node

Kelder

Vicente‐Steijn

Poelmann

et al. 2018

The Anatomical Record

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Development and evolution of the metazoan heart

Poelmann

Groot

2019

Developmental Dynamics

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The mechanisms of the evolution and development of the heart in metazoans are highlighted, starting with the evolutionary origin of the contractile cell, supposedly the precursor of cardiomyocytes. The last eukaryotic common ancestor is likely a combination of several cellular organisms containing their specific metabolic pathways and genetic signaling networks. During evolution, these tool kits diversified. Shared parts of these conserved tool kits act in the development and functioning of pumping hearts and open or closed circulations in such diverse species as arthropods, mollusks, and chordates. The genetic tool kits became more complex by gene duplications, addition of epigenetic modifications, influence of environmental factors, incorporation of viral genomes, cardiac changes necessitated by air‐breathing, and many others. We evaluate mechanisms involved in mollusks in the formation of three separate hearts and in arthropods in the formation of a tubular heart. A tubular heart is also present in embryonic stages of chordates, providing the septated four‐chambered heart, in birds and mammals passing through stages with first and second heart fields. The four‐chambered heart permits the formation of high‐pressure systemic and low‐pressure pulmonary circulation in birds and mammals, allowing for high metabolic rates and maintenance of body temperature. Crocodiles also have a (nearly) separated circulation, but their resting temperature conforms with the environment. We argue that endothermic ancestors lost the capacity to elevate their body temperature during evolution, resulting in ectothermic modern crocodilians. Finally, a clinically relevant paragraph reviews the occurrence of congenital cardiac malformations in humans as derailments of signaling pathways during embryonic development.

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Rho-ROCK Signaling in Normal Physiology and as a Key Player in Shaping the Tumor Microenvironment

Porazinski

Parkin

2020

Advances in Experimental Medicine and Biology

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RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node

Abstract: RHOA-ROCK signalling is involved in establishing the right-sided SAN as the definitive pacemaker of the heart and restricts typical pacemaker gene expression to the right side of the sinus venosus myocardium.

Cited by 19 publications

References 45 publications

Disruption of RHOA‐ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node

Disruption of RHOA‐ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node

Development and evolution of the metazoan heart

Rho-ROCK Signaling in Normal Physiology and as a Key Player in Shaping the Tumor Microenvironment

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