Aplexone targets the HMG-CoA reductase pathway and differentially regulates arteriovenous angiogenesis

Choi, Jayoung; Mouillesseaux, Kevin P.; Wang, Zhiming; Fiji, Hannah D.G.; Kinderman, Sape S.; Otto, G.; Geisler, Robert; Kwon, Ohyun; Chen, Jau-Nian

doi:10.1242/dev.054049

Cited by 63 publications

(49 citation statements)

References 40 publications

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“…S2). The CV primordia initially formed just beneath the caudal artery (CA) at 24 hpf, as previously reported (Choi et al, 2011). Then, the ECs sprouted from the CV primordia to migrate ventrally at 28 hpf, and formed a CV plexus (CVP) at 36 hpf.…”

Section: Visualization Of β-Catenin Transcriptional Activity In Ecs Dsupporting

confidence: 61%

“…Crucial role of β-catenin-dependent transcription in CV formation CV formation involves venous fate specification/differentiation, venous sprouting and remodeling, making it suitable for studying venous vessel formation (Choi et al, 2011;Kim et al, 2012;Wiley et al, 2011). To address the role of β-catenin in CV formation, we first analyzed CV formation during development (supplementary material Fig.…”

Section: Visualization Of β-Catenin Transcriptional Activity In Ecs Dmentioning

confidence: 99%

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β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

et al. 2015

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β-catenin regulates the transcription of genes involved in diverse biological processes, including embryogenesis, tissue homeostasis and regeneration. Endothelial cell (EC)-specific gene-targeting analyses in mice have revealed that β-catenin is required for vascular development. However, the precise function of β-cateninmediated gene regulation in vascular development is not well understood, since β-catenin regulates not only gene expression but also the formation of cell-cell junctions. To address this question, we have developed a novel transgenic zebrafish line that allows the visualization of β-catenin transcriptional activity specifically in ECs and discovered that β-catenin-dependent transcription is central to the bone morphogenetic protein (Bmp)-mediated formation of venous vessels. During caudal vein (CV) formation, Bmp induces the expression of aggf1, a putative causative gene for KlippelTrenaunay syndrome, which is characterized by venous malformation and hypertrophy of bones and soft tissues. Subsequently, Aggf1 potentiates β-catenin transcriptional activity by acting as a transcriptional co-factor, suggesting that Bmp evokes β-catenin-mediated gene expression through Aggf1 expression. Bmp-mediated activation of β-catenin induces the expression of Nr2f2 (also known as Coup-TFII), a member of the nuclear receptor superfamily, to promote the differentiation of venous ECs, thereby contributing to CV formation. Furthermore, β-catenin stimulated by Bmp promotes the survival of venous ECs, but not that of arterial ECs. Collectively, these results indicate that Bmp-induced activation of β-catenin through Aggf1 regulates CV development by promoting the Nr2f2-dependent differentiation of venous ECs and their survival. This study demonstrates, for the first time, a crucial role of β-catenin-mediated gene expression in the development of venous vessels.

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Section: Visualization Of β-Catenin Transcriptional Activity In Ecs Dsupporting

confidence: 61%

Section: Visualization Of β-Catenin Transcriptional Activity In Ecs Dmentioning

confidence: 99%

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

et al. 2015

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“…During normal vascular formation, the caudal vasculature beyond the yolk extension undergoes morphological changes over the first 5 days post fertilization (dpf) to eventually form a single caudal aorta and 1 caudal vein (34,35). This begins with a caudal vascular plexus, which is formed by 48 hpf.…”

Section: Resultsmentioning

confidence: 99%

RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity

Kawasaki¹,

Aegerter²,

Fevurly³

et al. 2014

J. Clin. Invest.

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Vascular malformations are linked to mutations in RAS p21 protein activator 1 (RASA1, also known as p120RasGAP); however, due to the global expression of this gene, it is unclear how these mutations specifically affect the vasculature. Here, we tested the hypothesis that RASA1 performs a critical effector function downstream of the endothelial receptor EPHB4. In zebrafish models, we found that either RASA1 or EPHB4 deficiency induced strikingly similar abnormalities in blood vessel formation and function. Expression of WT EPHB4 receptor or engineered receptors with altered RASA1 binding revealed that the ability of EPHB4 to recruit RASA1 is required to restore blood flow in EPHB4-deficient animals. Analysis of EPHB4-deficient zebrafish tissue lysates revealed that mTORC1 is robustly overactivated, and pharmacological inhibition of mTORC1 in these animals rescued both vessel structure and function. Furthermore, overexpression of mTORC1 in endothelial cells exacerbated vascular phenotypes in animals with reduced EPHB4 or RASA1, suggesting a functional EPHB4/ RASA1/mTORC1 signaling axis in endothelial cells. Tissue samples from patients with arteriovenous malformations displayed strong endothelial phospho-S6 staining, indicating increased mTORC1 activity. These results indicate that deregulation of EPHB4/RASA1/mTORC1 signaling in endothelial cells promotes vascular malformation and suggest that mTORC1 inhibitors, many of which are approved for the treatment of certain cancers, should be further explored as a potential strategy to treat patients with vascular malformations.

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“…We focused on the ISVs and on the caudal vein plexus (CVP) (Fig. 6A), which form by this process in zebrafish (Choi et al, 2011;Zhong, 2005). In control embryos, the ISV sprouted from the dorsal aorta at 24 hpf by extending numerous long filopodia (Fig.…”

Section: S1p 1 Negatively Regulates Sprouting Angiogenesismentioning

confidence: 99%

“…Unlike the ISV, the CVP forms as a very dense capillary network (Choi et al, 2011;Wiley et al, 2011). To maintain this structure and prevent fusion of forming vessels, inhibition of excessive filopodia formation is crucial.…”

Section: S1p 1 Negatively Regulates Sprouting Angiogenesismentioning

confidence: 99%

S1P1 inhibits sprouting angiogenesis during vascular development

et al. 2012

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SUMMARYCoordination between the vascular system and forming organs is essential for proper embryonic development. The vasculature expands by sprouting angiogenesis, during which tip cells form filopodia that incorporate into capillary loops. Although several molecules, such as vascular endothelial growth factor A (Vegfa), are known to induce sprouting, the mechanism that terminates this process to ensure neovessel stability is still unknown. Sphingosine-1-phosphate receptor 1 (S1P 1 ) has been shown to mediate interaction between endothelial and mural cells during vascular maturation. In vitro studies have identified S1P 1 as a pro-angiogenic factor. Here, we show that S1P 1 acts as an endothelial cell (EC)-autonomous negative regulator of sprouting angiogenesis during vascular development. Severe aberrations in vessel size and excessive sprouting found in limbs of S1P 1 -null mouse embryos before vessel maturation imply a previously unknown, mural cell-independent role for S1P 1 as an anti-angiogenic factor. A similar phenotype observed when S1P 1 expression was blocked specifically in ECs indicates that the effect of S1P 1 on sprouting is EC-autonomous. Comparable vascular abnormalities in S1p 1 knockdown zebrafish embryos suggest cross-species evolutionary conservation of this mechanism. Finally, genetic interaction between S1P 1 and Vegfa suggests that these factors interplay to regulate vascular development, as Vegfa promotes sprouting whereas S1P 1 inhibits it to prevent excessive sprouting and fusion of neovessels. More broadly, because S1P, the ligand of S1P 1 , is blood-borne, our findings suggest a new mode of regulation of angiogenesis, whereby blood flow closes a negative feedback loop that inhibits sprouting angiogenesis once the vascular bed is established and functional.

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Aplexone targets the HMG-CoA reductase pathway and differentially regulates arteriovenous angiogenesis

Cited by 63 publications

References 40 publications

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity

S1P1 inhibits sprouting angiogenesis during vascular development

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