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Angiogenesis
Published in: Angiogenesis 1/2021

Open Access 01-02-2021 | Original Paper

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

Authors: H. H. Pulkkinen, M. Kiema, J. P. Lappalainen, A. Toropainen, M. Beter, A. Tirronen, L. Holappa, H. Niskanen, M. U. Kaikkonen, S. Ylä-Herttuala, Johanna P. Laakkonen

Published in: Angiogenesis | Issue 1/2021

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Abstract

The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.
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Literature
1.
Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11(2):109–119PubMedPubMedCentral
2.
3.
De Palma M, Biziato D, Petrova TV (2017) Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 17(8):457–474PubMed
4.
5.
Laakkonen JP, Yla-Herttuala S (2015) Recent advancements in cardiovascular gene therapy and vascular biology. Hum Gene Ther 26(8):518–524PubMed
6.
Hartikainen J, Hassinen I, Hedman A et al (2017) Adenoviral intramyocardial VEGF-DDeltaNDeltaC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J 38(33):2547–2555PubMedPubMedCentral
7.
Schweighofer B, Testori J, Sturtzel C et al (2009) The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammation. Thromb Haemost 102(3):544–554PubMedPubMedCentral
8.
Kaikkonen MU, Niskanen H, Romanoski CE et al (2014) Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization. Nucleic Acids Res 42(20):12570–12584PubMedPubMedCentral
9.
Laakkonen JP, Lappalainen JP, Theelen TL et al (2017) Differential regulation of angiogenic cellular processes and claudin-5 by histamine and VEGF via PI3K-signaling, transcription factor SNAI2 and interleukin-8. Angiogenesis 20(1):109–124PubMed
10.
Cai J, Pardali E, Sanchez-Duffhues G, ten Dijke P (2012) BMP signaling in vascular diseases. FEBS Lett 586(14):1993–2002PubMed
11.
Maddaluno L, Rudini N, Cuttano R et al (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496PubMed
12.
Wang RN, Green J, Wang Z et al (2014) Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis 1(1):87–105PubMedPubMedCentral
13.
Yang X, Castilla LH, Xu X et al (1999) Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development 126(8):1571–1580PubMed
14.
Kaartinen V, Dudas M, Nagy A, Sridurongrit S, Lu MM, Epstein JA (2004) Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells. Development 131(14):3481–3490PubMed
15.
Lan Y, Liu B, Yao H et al (2007) Essential role of endothelial Smad4 in vascular remodeling and integrity. Mol Cell Biol 27(21):7683–7692PubMedPubMedCentral
16.
El-Bizri N, Guignabert C, Wang L et al (2008) SM22alpha-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis. Development 135(17):2981–2991PubMedPubMedCentral
17.
Rothhammer T, Bataille F, Spruss T, Eissner G, Bosserhoff AK (2007) Functional implication of BMP4 expression on angiogenesis in malignant melanoma. Oncogene 26(28):4158–4170PubMed
18.
Yao Y, Watson AD, Ji S, Bostrom KI (2009) Heat shock protein 70 enhances vascular bone morphogenetic protein-4 signaling by binding matrix gla protein. Circ Res 105(6):575–584PubMedPubMedCentral
19.
Zuo WH, Zeng P, Chen X, Lu YJ, Li A, Wu JB (2016) Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways. Sci Rep 6:37499PubMedPubMedCentral
20.
Benn A, Hiepen C, Osterland M, Schutte C, Zwijsen A, Knaus P (2017) Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor-dependent signaling pathways balance stalk vs. tip cell competence. FASEB J 31(11):4720–4733PubMedPubMedCentral
21.
Krispin S, Stratman AN, Melick CH et al (2018) Growth differentiation factor 6 promotes vascular stability by restraining vascular endothelial growth factor signaling. Arterioscler Thromb Vasc Biol 38(2):353–362PubMed
22.
Miyazono K, Kamiya Y, Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147(1):35–51PubMed
23.
Kim M, Yoon S, Lee S et al (2012) Gremlin-1 induces BMP-independent tumor cell proliferation, migration, and invasion. PLoS ONE 7(4):e35100PubMedPubMedCentral
24.
Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Investig 52(11):2745–2756PubMed
25.
Gough PJ, Greaves DR, Gordon S (1998) A naturally occurring isoform of the human macrophage scavenger receptor (SR-A) gene generated by alternative splicing blocks modified LDL uptake. J Lipid Res 39(3):531–543PubMed
26.
Niskanen H, Tuszynska I, Zaborowski R et al (2018) Endothelial cell differentiation is encompassed by changes in long range interactions between inactive chromatin regions. Nucleic Acids Res 46(4):1724–1740PubMed
27.
Tabula Muris Consortium (2018) Overall coordination, Logistical coordination, et al. Single-cell transcriptomics of 20 mouse organs creates a tabula muris. Nature 562(7727):367–372
28.
Abramoff MD, Magalhaes PJ, Ram SJ (2004) Image processing with ImageJ. Biophotonics Int 11(7):36–42
29.
Nakatsu MN, Hughes CC (2008) An optimized three-dimensional in vitro model for the analysis of angiogenesis. Methods Enzymol 443:65–82PubMed
30.
Roh SY, Park JC (2017) The role of nuclear factor I-C in tooth and bone development. J Korean Assoc Oral Maxillofac Surg 43(2):63–69PubMedPubMedCentral
31.
32.
Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM (2015) TGF-beta/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res 3:15005PubMedPubMedCentral
33.
Clementi C, Tripurani SK, Large MJ et al (2013) Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans. PLoS Genet 9(11):e1003863PubMedPubMedCentral
34.
Duong TB, Ravisankar P, Song YC et al (2018) Nr2f1a balances atrial chamber and atrioventricular canal size via BMP signaling-independent and -dependent mechanisms. Dev Biol 434(1):7–14PubMed
35.
Schafer G, Wissmann C, Hertel J, Lunyak V, Hocker M (2008) Regulation of vascular endothelial growth factor D by orphan receptors hepatocyte nuclear factor-4 alpha and chicken ovalbumin upstream promoter transcription factors 1 and 2. Cancer Res 68(2):457–466PubMed
36.
Sati L, Zeiss C, Yekkala K, Demir R, McGrath J (2015) Expression of the CTCFL gene during mouse embryogenesis causes growth retardation, postnatal lethality, and dysregulation of the transforming growth factor beta pathway. Mol Cell Biol 35(19):3436–3445PubMedPubMedCentral
37.
Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86(2):236–242PubMedPubMedCentral
38.
39.
Noguera-Troise I, Daly C, Papadopoulos NJ et al (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037PubMed
40.
Ridgway J, Zhang G, Wu Y et al (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444(7122):1083–1087PubMed
41.
van Nieuw Amerongen GP, Koolwijk P, Versteilen A, van Hinsbergh VW (2003) Involvement of RhoA/rho kinase signaling in VEGF-induced endothelial cell migration and angiogenesis in vitro. Arterioscler Thromb Vasc Biol 23(2):211–217PubMed
42.
Hagihara M, Endo M, Hata K et al (2011) Neogenin, a receptor for bone morphogenetic proteins. J Biol Chem 286(7):5157–5165PubMed
43.
Wang YK, Yu X, Cohen DM et al (2012) Bone morphogenetic protein-2-induced signaling and osteogenesis is regulated by cell shape, RhoA/ROCK, and cytoskeletal tension. Stem Cells Dev 21(7):1176–1186PubMed
44.
Lai D, Yang X (2013) BMP4 is a novel transcriptional target and mediator of mammary cell migration downstream of the hippo pathway component TAZ. Cell Signal 25(8):1720–1728PubMed
45.
Hansen CG, Moroishi T, Guan KL (2015) YAP and TAZ: a nexus for hippo signaling and beyond. Trends Cell Biol 25(9):499–513PubMedPubMedCentral
46.
Wang X, Freire Valls A, Schermann G et al (2017) YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev Cell 42(5):462-478.e7PubMed
47.
48.
Kim J, Kim YH, Kim J et al (2017) YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Investig 127(9):3441–3461PubMed
49.
Yang N, Morrison CD, Liu P et al (2012) TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin. Cell Cycle 11(15):2922–2930PubMedPubMedCentral
50.
Heallen T, Zhang M, Wang J et al (2011) Hippo pathway inhibits wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332(6028):458–461PubMedPubMedCentral
51.
Zhang H, Liu CY, Zha ZY et al (2009) TEAD transcription factors mediate the function of TAZ in cell growth and epithelial–mesenchymal transition. J Biol Chem 284(20):13355–13362PubMedPubMedCentral
52.
Zhang H, Pasolli HA, Fuchs E (2011) Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci USA 108(6):2270–2275PubMed
53.
Li B, Wang H, Qiu G, Su X, Wu Z (2016) Synergistic effects of vascular endothelial growth factor on bone morphogenetic proteins induced bone formation in vivo: influencing factors and future research directions. Biomed Res Int 2016:2869572PubMedPubMedCentral
54.
de Jesus Perez VA, Alastalo TP, Wu JC et al (2009) Bone morphogenetic protein 2 induces pulmonary angiogenesis via wnt-beta-catenin and wnt-RhoA-Rac1 pathways. J Cell Biol 184(1):83–99PubMedPubMedCentral
55.
Darby S, Cross SS, Brown NJ, Hamdy FC, Robson CN (2008) BMP-6 over-expression in prostate cancer is associated with increased id-1 protein and a more invasive phenotype. J Pathol 214(3):394–404PubMed
56.
Langenfeld EM, Langenfeld J (2004) Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res 2(3):141–149PubMed
57.
58.
59.
Mouillesseaux KP, Wiley DS, Saunders LM et al (2016) Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun 7:13247PubMedPubMedCentral
60.
Suzuki Y, Montagne K, Nishihara A, Watabe T, Miyazono K (2008) BMPs promote proliferation and migration of endothelial cells via stimulation of VEGF-A/VEGFR2 and angiopoietin-1/Tie2 signalling. J Biochem 143(2):199–206PubMed
61.
Scharpfenecker M, van Dinther M, Liu Z et al (2007) BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 120(Pt 6):964–972PubMed
62.
Albini A, Bruno A, Noonan DM, Mortara L (2018) Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol 9:527PubMedPubMedCentral
63.
Newman AC, Nakatsu MN, Chou W, Gershon PD, Hughes CC (2011) The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol Biol Cell 22(20):3791–3800PubMedPubMedCentral
64.
65.
66.
Zhang X, Zhao H, Li Y et al (2018) The role of YAP/TAZ activity in cancer metabolic reprogramming. Mol Cancer 17(1):134–018PubMedPubMedCentral
67.
Welch-Reardon KM, Ehsan SM, Wang K et al (2014) Angiogenic sprouting is regulated by endothelial cell expression of slug. J Cell Sci 127(Pt 9):2017–2028PubMedPubMedCentral
68.
Valdimarsdottir G, Goumans MJ, Rosendahl A et al (2002) Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation 106(17):2263–2270PubMed
69.
70.
Wei Q, Holle A, Li J et al (2020) BMP-2 signaling and mechanotransduction synergize to drive osteogenic differentiation via YAP/TAZ. Adv Sci (Weinh) 7(15):1902931
71.
Kim SM, Ye S, Rah SY et al (2016) RhBMP-2 activates hippo signaling through RASSF1 in esophageal cancer cells. Sci Rep 6:26821PubMedPubMedCentral
72.
Metadata
Title
BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF
Authors
H. H. Pulkkinen
M. Kiema
J. P. Lappalainen
A. Toropainen
M. Beter
A. Tirronen
L. Holappa
H. Niskanen
M. U. Kaikkonen
S. Ylä-Herttuala
Johanna P. Laakkonen
Publication date
01-02-2021
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 1/2021
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-020-09748-4

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