BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II

Kim, Jai-Hyun; Peacock, Matthew; George, Steven C.; Hughes, Christopher C.W.

doi:10.1007/s10456-012-9277-x

Cited by 53 publications

(50 citation statements)

References 57 publications

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“…To our knowledge, we provide here the first description of TGFβ1 gradients in the brain, which direct the dorsalventral patterning of CNS vasculature. Numerous reports describe an important role for TGFβ and BMP signaling in sprouting angiogenesis (Kim et al, 2012;Larrivée et al, 2012;Liu et al, 2009;Moya et al, 2012). However, the specific role of TGFβ1 in brain angiogenesis (vascular sprouting/branching) was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

“…TGFBR1/ALK5 with TGFBR2 induces phosphorylation of Smad2/3 complexes. In endothelial cells, an alternative type I receptor, ALK1, is thought to complex with BMPR2 to induce phosphorylation of Smad1/ 5/8, which interact with Notch effectors to promote stalk cell differentiation (Kim et al, 2012;Larrivée et al, 2012;Li et al, 2011;Moya et al, 2012). Although BMP9 and BMP10 are believed to be the major ALK1 ligands, TGFβ can activate ALK5-TGFBR2 (Smad2/3) and ALK1-BMPR2 (Smad1/5/8) in vitro, and in certain contexts in vivo (Pardali et al, 2010).…”

Section: Pericyte Proliferation In Itgb8δne Embryosmentioning

confidence: 99%

“…As they grow, nascent sprouts extend filopodia toward sources of VEGF (James et al, 2009;Ruhrberg et al, 2002), and are specified into tip and stalk cells by Dll4/Notch-mediated lateral inhibition (Phng and Gerhardt, 2009). Initial sprouting and patterning is further regulated by signaling systems, including netrin (Freitas et al, 2008), ephrin (Sawamiphak et al, 2010;Wang et al, 2010), BMP (Kim et al, 2012;Larrivée et al, 2012;Moya et al, 2012), Wnt/β-Catenin (Corada et al, 2010;Gore et al, 2011) and angiopoietin (Fagiani and Christofori, 2013). Once primary CNS angiogenesis is complete, sprouting angiogenesis is suppressed and new vessels are stabilized (Gaengel et al, 2012;Jung et al, 2012;Shoham et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

et al. 2014

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Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb ret/ret mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.

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Section: Discussionmentioning

confidence: 99%

Section: Pericyte Proliferation In Itgb8δne Embryosmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

et al. 2014

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“…1106-bp (−929 nt to +176 nt respective to the transcription start site) long region of the human EFNB2 promoter was a kind gift from Dr. Christopher CW Hughes (University of California, Irvine, CA, USA) and it has been thoroughly characterized in another study. 45 The Renilla luciferase construct (pRL-TK) was purchased from Promega Corp (Madison, WI, USA). The wild-type p53 (pCMV-p53) and the mutant p53 (pCMV-R175H and pCMV-R273H) expression plasmids were a kind gift from Dr. Bert Vogelstein (Johns Hopkins University, Baltimore, MD, USA) and full-length EFNB2 cDNA clone was purchased from Origene Technologies (Rockville, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

et al. 2015

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Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumors.

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“…Increased Pai1 suggests increased TGFβ signaling following endothelial deletion of Rbpj. Mutations in TGFβ pathway members are associated with AVMs in humans, mice and zebrafish (Corti et al, 2011;Johnson et al, 1996;Kim et al, 2012;McAllister et al, 1994;Park et al, 2008Park et al, , 2009Urness et al, 2000). Recently, TGFβ and Notch were shown to synergistically regulate retinal vascular morphogenesis (Larrivee et al, 2012) and BAVM formation (Yao et al, 2013) in mice.…”

Section: Loss Of Endothelial Rbpj Alters a Downstream Tgfβ Effector Imentioning

confidence: 99%

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

et al. 2014

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Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification by promoting arterial, as opposed to venous, endothelial cell (EC) fate. To understand the essential role of endothelial Notch signaling in postnatal AV organization, we used inducible Cre-loxP recombination to delete Rbpj, a mediator of canonical Notch signaling, from postnatal ECs in mice. Deletion of endothelial Rbpj from birth resulted in features of AVMs by P14, including abnormal AV shunting and tortuous vessels in the brain, intestine and heart. We further analyzed brain AVMs, as they pose particular health risks. Consistent with AVM pathology, we found cerebral hemorrhage, hypoxia and necrosis, and neurological deficits. AV shunts originated from capillaries (and possibly venules), with the earliest detectable morphological abnormalities in AV connections by P8. Prior to AV shunt formation, alterations in EC gene expression were detected, including decreased Efnb2 and increased Pai1, which encodes a downstream effector of TGFβ signaling. After AV shunts had formed, whole-mount immunostaining showed decreased Efnb2 and increased Ephb4 expression within AV shunts, suggesting that ECs were reprogrammed from arterial to venous identity. Deletion of Rbpj from adult ECs led to tortuosities in gastrointestinal, uterine and skin vascular beds, but had mild effects in the brain. Our results demonstrate a temporal requirement for Rbpj in postnatal ECs to maintain proper artery, capillary and vein organization and to prevent abnormal AV shunting and AVM pathogenesis.

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BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II

Cited by 53 publications

References 57 publications

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

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