BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses

Young, Kira; Tweedie, Eric; Conley, Barbara A.; Ames, Jacquelyn J.; FitzSimons, MaryLynn; Brooks, Peter C.; Liaw, Lucy; Vary, Calvin P.H.

doi:10.1371/journal.pone.0122892

Cited by 39 publications

(39 citation statements)

References 124 publications

(168 reference statements)

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“…The Notch, VEGF, and BMP signaling pathways have been shown to play important roles in regulating vascular sprouting and tip cell formation during angiogenesis (9,(12)(13)(14). One report showed that BMP9 crosstalks with the Hippo pathway by repressing YAP target genes in endothelial cells (47). It seems possible that, in turn, YAP and TAZ could regulate BMP, Notch, and other pathways to control vascular development.…”

Section: Cell Autonomous Function Of Yap/taz Vascular Development In mentioning

confidence: 99%

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Sakabe

Fan

Odaka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

168

157

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Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by Lats1/2-deletion blocked endothelial migration and phenocopied Yap/Taz-deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis.A ngiogenesis is a process of growth and remodeling in vascular networks that is essential for normal development. In adulthood, angiogenesis is activated as a reparative process, for example, during wound healing (1, 2). Aberrantly regulated angiogenesis can also be a component of disease (3) and can play a key role in tumor growth and metastasis (4), inflammatory diseases (5), diabetic retinopathy, and retinopathy of prematurity (6).Retinal angiogenesis in mice begins at postnatal day 0 (P0). The retinal vasculature initiates its expansion from the optic nerve head and migrates outwards along a preexisting network of astrocytes (7,8). This results in the formation of the superficial vascular plexus within the retinal ganglion cell layer during the first 8 d (9, 10). Endothelial cells (ECs) then migrate along nerve fibers to establish deep and intermediate vascular layers (9,11). Cell proliferation and migration are essential for angiogenesis and these cell responses are regulated by many different signaling pathways, including the VEGF, Notch, Wnt, FGF, BMP, and integrin signaling responses (9, 12-16). VEGFA and CDC42 are known to regulate extension of the angiogenic front and filopodia formation in angiogenic tip cells (2,17,18).The Hippo signaling pathway is an evolutionarily conserved, pivotal regulator of cell proliferation and organogenesis. YAP and TAZ are key components of the Hippo signaling pathway and function as transcription cofactors that regulate downstream gene expression via association with DNA binding proteins such as 20). Loss of Hippo signaling can drive the expression of genes that regulate cell proliferation and survival (diap1, bantam, cyclin E, and E2F1), the Hippo pathway (Kibra, Crb, and Fj), and cell-cell interaction (E-Cadherin, Serrate, Wingless, and Vein) (20). The activity of YAP and TAZ is regulated by the LATS1 and LATS2 kinases. These kinases phosphorylate YAP and TAZ, thus preventing their nuclear translocation and regulating transcriptional activity. Although the function of YAP and TAZ in the ...

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Section: Cell Autonomous Function Of Yap/taz Vascular Development In mentioning

confidence: 99%

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Sakabe

Fan

Odaka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

168

157

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“…We speculate that ALK1/endoglin signaling may be permissive for this planar polarization or may regulate cell-matrix interactions to allow migration against the direction of flow. In support of these ideas, ENG expression alters actin cytoskeletal organization [201], and BMP9 treatment increases the abundance of the actin-polymerizing protein, zyxin [202], in EC focal adhesions [203, 204]. Zyxin and zyxin-related protein-1 both bind to endoglin via its C-terminal intracellular domain [201, 203], and mechanical force or loss of endoglin results in accumulation of zyxin in focal adhesions [202, 204].…”

Section: Cellular Mechanisms Of Avm Developmentmentioning

confidence: 99%

“…In support of these ideas, ENG expression alters actin cytoskeletal organization [201], and BMP9 treatment increases the abundance of the actin-polymerizing protein, zyxin [202], in EC focal adhesions [203, 204]. Zyxin and zyxin-related protein-1 both bind to endoglin via its C-terminal intracellular domain [201, 203], and mechanical force or loss of endoglin results in accumulation of zyxin in focal adhesions [202, 204]. These data suggest that zyxin may be sequestered by binding to endoglin, and that either BMP9/ALK1 activation or mechanical force disrupts this interaction to allow relocalization to and maturation of focal adhesions, which are integral to cell migration.…”

Section: Cellular Mechanisms Of Avm Developmentmentioning

confidence: 99%

“…These data suggest that zyxin may be sequestered by binding to endoglin, and that either BMP9/ALK1 activation or mechanical force disrupts this interaction to allow relocalization to and maturation of focal adhesions, which are integral to cell migration. BMP9 may also regulate zyxin at the level of transcription: both BMP9 and mechanical force induce yes-associated protein-1 (YAP1) translocation to the nucleus [204, 205], where it can act as a transcriptional coactivator to induce zyxin expression [206]. …”

Section: Cellular Mechanisms Of Avm Developmentmentioning

confidence: 99%

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ALK1 signaling in development and disease: new paradigms

Roman

Hinck

2017

Cell. Mol. Life Sci.

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Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.

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“…Moreover, in endoglin null embryos, conditional expression of an endoglin transgene in either endothelial or smooth muscle cells partially rescues smooth muscle cell differentiation and investment of the developing E9.5-E10.5 dorsal aorta (Mancini et al, 2009). Thus, endoglin's functions during angiogenesis are complex, likely comprising both cell-autonomous (e.g., adhesive, TGFβ/BMP signaling), autocrine, and paracrine (e.g., regulation of chemokine and matrikine expression (Young et al, 2012; Young et al, 2015)) signaling roles in multiple cell types that contribute to embryonic blood vessel development. However, the requirement for endoglin expression in vascular cell precursors for vessel formation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Endoglin is required in Pax3-derived cells for embryonic blood vessel formation

Young

Krebs

Tweedie

et al. 2016

Developmental Biology

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Mutations in endoglin, a TGFβ/BMP coreceptor, are causal for hereditary hemorrhagic telangiectasia (HHT). Endoglin-null (Eng−/−) mouse embryos die at embryonic day (E)10.5-11.5 due to defects in angiogenesis. In part, this is due to an absence of vascular smooth muscle cell differentiation and vessel investment. Prior studies from our lab and others have shown the importance of endoglin expression in embryonic development in both endothelial cells and neural crest stem cells. These studies support the hypothesis that endoglin may play cell-autonomous roles in endothelial and vascular smooth muscle cell precursors. However, the requirement for endoglin in vascular cell precursors remains poorly defined. Our objective was to specifically delete endoglin in neural crest- and somite-derived Pax3-positive vascular precursors to understand the impact on somite progenitor cell contribution to embryonic vascular development. Pax3Cre mice were crossed with Eng+/− mice to obtain compound mutant Pax3Cre/+;Eng+/− mice. These mice were then crossed with homozygous endoglin LoxP-mutated (EngLoxP/LoxP) mice to conditionally delete the endoglin gene in specific lineages that contribute to endothelial and smooth muscle constituents of developing embryonic vessels. Pax3Cre/+;EngLoxP/− mice showed a variety of vascular defects at E10.5, and none of these mice survived past E12.5. Embryos analyzed at E10.5 showed malformations suggestive of misdirection of the intersomitic vessels. The dorsal aorta showed significant dilation with associated vascular smooth muscle cells exhibiting disorganization and enhanced expression of smooth muscle differentiation proteins, including smooth muscle actin. These results demonstrate a requirement for endoglin in descendants of Pax3-expressing vascular cell precursors, and thus provides new insight into the cellular basis underlying adult vascular diseases such as HHT.

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BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses

Cited by 39 publications

References 124 publications

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

ALK1 signaling in development and disease: new paradigms

Endoglin is required in Pax3-derived cells for embryonic blood vessel formation

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