Shear Stress–Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos

Li, Rongsong; Beebe, Tyler; Jen, Nelson; Yu, Fei; Takabe, Wakako; Harrison, Michael R.; Cao, Hung; Lee, Juhyun; Yang, Hongbo; Han, Peidong; Wang, Kevin; Shimizu, Hirohito; Chen, Jau-Nian; Lien, Ching Ling; Neil, C.; Hsiai, Tzung K.

doi:10.1161/atvbaha.114.303345

Cited by 58 publications

(55 citation statements)

References 38 publications

(40 reference statements)

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“…They have an immune system, bones, and digestive, nervous and cardiovascular systems. In addition to developmental process and disease modeling, transgenic mutants have provided the opportunity for optogenetic control of cardiac function[34], hemodynamic stress-mediated developmental genes for vascular repair[10], and a platform for in vivo drug discovery[17]. …”

Section: Discussionmentioning

confidence: 99%

“…The average length of an adult fish is at 2 to 4 cm, accessible for relatively low-cost and high-throughput small molecule screening[9]. Their physiological complexity also provides conserved models of human disease for in vivo validation studies[10]. The biological characteristics of zebrafish are suitable for toxicity testing, including eco-toxicology[11].…”

Section: Introductionmentioning

confidence: 99%

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Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening

Zhang

Beebe²,

Jen³

et al. 2015

Biosensors and Bioelectronics

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Flexible electronics are the next generation of sensors for mobile health and implantation. Zebrafish (Danio rerio) is an emergent strategy for pre-clinical drug development and toxicity testing. To address the confounding effects from sedation of fish and removal from the aquatic habitat for micro-electrocardiogram (μECG) measurements, we developed waterproof and wearable sensors to uncover the circadian variation in heart rate (HR) and heart rate variability (HRV)[1]. The parylene-C based ECG sensor consisted of an ultra-soft silicone integrated jacket designed to wrap around the fish during swimming. The Young’s modulus of this silicone jacket matched with the fish surface, and an extended parylene cable connected the underwater chest electrodes with the out-of water electronics. In addition, embedded micro-glass spheres in the silicone effectively reduced the effective density of the jacket to ~ 1 g·cm−3. These innovations enabled physiological ECG telemetry in the fish’s natural habitat without the need for sedation. Furthermore, a set of non-linear signal processing techniques filtered out the breathing and electromagnetic artifacts from the recorded signals. We observed a reduction in mean HR and an increase in HRV over 24 hours at 10 dpa, accompanied by QT prolongation as well as diurnal variations, followed by normalization in mean HR and QT intervals at 26 days post ventricular amputation (dpa). We revealed Amiodarone-mediated QTc prolongation, HR reduction and HRV increase otherwise masked by sedation. The novel features of the flexible silicon jacket for μECG telemetry unraveled the biological clock and normalization of QT intervals at 26 dpa, providing the first evidence of new physiological phenomena during cardiac injury and repair as well as cardiac drug-mediated aberrant rhythms. Thus, the light weight and waterproof design holds promise to advance the next generation of mobile health and drug discovery.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening

Zhang

Beebe²,

Jen³

et al. 2015

Biosensors and Bioelectronics

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“…OSS is known to activate the Wnt/β-catenin signaling pathway in blood ECs (Li et al 2014;Kim et al 2015). We wanted to determine whether this relationship is conserved in LECs.…”

Section: Wnt/β-catenin Signaling Is Necessary and Sufficient For Oss-mentioning

confidence: 99%

Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves

et al. 2016

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Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2.

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“…Shear stress has been found to regulate the canonical Wnt pathway in endothelial cells, leading to the increased expression of angiopoietin-2, a protein involved in vascular development and repair, in human aortic endothelial cells (HAECs) (73). In patients with symptomatic aortic valve stenosis, modulators of the Wnt signaling pathway, including WIF-1, DKK-1, and sFRP-3, exhibit increased expression in calcified aortic valves, and some modulators positively correlate with valvular calcification, indicating their potential role as biomarkers of aortic valve stenosis (7).…”

Section: Wnt/b-cateninmentioning

confidence: 99%

Shear-Sensitive Genes in Aortic Valve Endothelium

Esmerats

Heath

2016

Antioxidants & Redox Signaling

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Significance: Currently, calcific aortic valve disease (CAVD) is only treatable through surgical intervention because the specific mechanisms leading to the disease remain unclear. In this review, we explore the forces and structure of the valve, as well as the mechanosensors and downstream signaling in the valve endothelium known to contribute to inflammation and valve dysfunction. Recent Advances: While the valvular structure enables adaptation to dynamic hemodynamic forces, these are impaired during CAVD, resulting in pathological systemic changes. Mechanosensing mechanisms-proteins, sugars, and membrane structures-at the surface of the valve endothelial cell relay mechanical signals to the nucleus. As a result, a large number of mechanosensitive genes are transcribed to alter cellular phenotype and, ultimately, induce inflammation and CAVD. Transforming growth factor-b signaling and Wnt/b-catenin have been widely studied in this context. Importantly, NADPH oxidase and reactive oxygen species/reactive nitrogen species signaling has increasingly been recognized to play a key role in the cellular response to mechanical stimuli. In addition, a number of valvular microRNAs are mechanosensitive and may regulate the progression of CAVD. Critical Issues: While numerous pathways have been described in the pathology of CAVD, no treatment options are available to avoid surgery for advanced stenosis and calcification of the aortic valve. More work must be focused on this issue to lead to successful therapies for the disease. Future Directions: Ultimately, a more complete understanding of the mechanisms within the aortic valve endothelium will lead us to future therapies important for treatment of CAVD without the risks involved with valve replacement or repair. Antioxid. Redox Signal. 25, 401-414.

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Shear Stress–Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos

Cited by 58 publications

References 38 publications

Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening

Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening

Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves

Shear-Sensitive Genes in Aortic Valve Endothelium

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