Abstract
Notch signaling is an evolutionarily conserved intercellular signaling pathway that plays numerous crucial roles in vascular development and physiology. Compelling evidence indicates that Notch signaling is vital for vascular morphogenesis including arterial and venous differentiation and endothelial tip and stalk cell specification during sprouting angiogenesis and also vessel maturation featured by mural cell differentiation and recruitment. Notch signaling is also required for vascular homeostasis in adults by keeping quiescent phalanx cells from re-entering cell cycle and by modulating the behavior of endothelial progenitor cells. We will summarize recent advances of Notch pathway in vascular biology with special emphasis on the underlying molecular mechanisms.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell, 2011, 146: 873–887
Herbert SP, Stainier DY. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol, 2011, 12: 551–564
Garcia A, Kandel JJ. Notch: a key regulator of tumor angiogenesis and metastasis. Histol Histopathol, 2012, 27: 151–156
Eilken HM, Adams RH. Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol, 2010, 22: 617–625
Benedito R, Hellstrom M. Notch as a hub for signaling in angiogenesis. Exp Cell Res, 2013, 319: 1281–1288
Patel-Hett S, D’Amore PA. Signal transduction in vasculogenesis and developmental angiogenesis. Int J Dev Biol, 2011, 55: 353–363
Dou GR, Wang L, Wang YS, Han H. Notch signaling in ocular vasculature development and diseases. Mol Med (Cambridge, Mass), 2012, 18: 47–55
Artavanis-Tsakonas S, Muskavitch MA. Notch: the past, the present, and the future. Curr Top Dev Biol, 2010, 92: 1–29
Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci, 2009, 66: 1631–1646
Guruharsha KG, Kankel MW, Artavanis-Tsakonas S. The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet, 2012, 13: 654–666
Djiane A, Krejci A, Bernard F, Fexova S, Millen K, Bray SJ. Dissecting the mechanisms of Notch induced hyperplasia. EMBO J, 2013, 32: 60–71
Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. Dynamic binding of RBPJ is determined by Notch signaling status. Genes Dev, 2013, 27: 1059–1071
Morini MF, Dejana E. Transcriptional regulation of arterial differentiation via Wnt, Sox and Notch. Curr Opin Hematol, 2014, 21: 229–234
Swift MR, Weinstein BM. Arterial-venous specification during development. Circ Res, 2009, 104: 576–588
Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev, 2004, 18: 901–911
Kokubo H, Miyagawa-Tomita S, Nakazawa M, Saga Y, Johnson RL. Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev Biol, 2005, 278: 301–309
Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J, Thurston G, Yancopoulos GD. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA, 2004, 101: 15949–15954
Kitagawa M, Hojo M, Imayoshi I, Goto M, Ando M, Ohtsuka T, Kageyama R, Miyamoto S. Hes1 and Hes5 regulate vascular remodeling and arterial specification of endothelial cells in brain vascular development. Mech Dev, 2013, 130: 458–466
Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ, Messina LM, Capobianco AJ, Werb Z, Wang R. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci USA, 2005, 102: 9884–9889
Murphy PA, Kim TN, Lu G, Bollen AW, Schaffer CB, Wang RA. Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med, 2012, 4: 117ra8
Quillien A, Moore JC, Shin M, Siekmann AF, Smith T, Pan L, Moens CB, Parsons MJ, Lawson ND. Distinct Notch signaling outputs pattern the developing arterial system. Development, 2014, 141: 1544–1552
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science, 1997, 275: 964–967
Zhang M, Malik AB, Rehman J. Endothelial progenitor cells and vascular repair. Curr Opin Hematol, 2014, 21: 224–228
Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science, 2008, 319: 195–198
Kwon SM, Eguchi M, Wada M, Iwami Y, Hozumi K, Iwaguro H, Masuda H, Kawamoto A, Asahara T. Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization. Circulation, 2008, 118: 157–165
Ii M, Takeshita K, Ibusuki K, Luedemann C, Wecker A, Eaton E, Thorne T, Asahara T, Liao JK, Losordo DW. Notch signaling regulates endothelial progenitor cell activity during recovery from arterial injury in hypercholesterolemic mice. Circulation, 2010, 121: 1104–1112
Wang L, Wang YC, Hu XB, Zhang BF, Dou GR, He F, Gao F, Feng F, Liang YM, Dou KF, Han H. Notch-RBP-J signaling regulates the mobilization and function of endothelial progenitor cells by dynamic modulation of CXCR4 expression in mice. PLoS ONE, 2009, 4: 0007572
Chen JY, Feng L, Zhang HL, Li JC, Yang XW, Cao XL, Liu L, Qin HY, Liang YM, Han H. Differential regulation of bone marrow-derived endothelial progenitor cells and endothelial outgrowth cells by the Notch signaling pathway. PLoS ONE, 2012, 7: e43643
Dou GR, Wang YC, Hu XB, Hou LH, Wang CM, Xu JF, Wang YS, Liang YM, Yao LB, Yang AG, Han H. RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J, 2008, 22: 1606–1617
Ribatti D, Crivellato E. “Sprouting angiogenesis”, a reappraisal. Dev Biol, 2012, 372: 157–165
Tung JJ, Tattersall IW, Kitajewski J. Tips, stalks, tubes: notch-mediated cell fate determination and mechanisms of tubulogenesis during angiogenesis. Cold Spring Harb Perspect Med, 2012, 2: a006601
Siekmann AF, Lawson ND. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature, 2007, 445: 781–784
Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A, Eichmann A. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA, 2007, 104: 3225–3230
Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell, 2009, 137: 1124–1135
Napp LC, Augustynik M, Paesler F, Krishnasamy K, Woiterski J, Limbourg A, Bauersachs J, Drexler H, Le Noble F, Limbourg FP. Extrinsic Notch ligand Delta-like 1 regulates tip cell selection and vascular branching morphogenesis. Circ Res, 2012, 110: 530–535
Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, Singh M, Chien M, Tan C, Hongo JA, de Sauvage F, Plowman G, Yan M. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature, 2006, 444: 1083–1087
Thurston G, Noguera-Troise I, Yancopoulos GD. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer, 2007, 7: 327–331
Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M, Biswas S, Turley H, Heikamp E, Hainfellner JA, Harris AL. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res, 2007, 67: 11244–11253
Garcia-Pascual CM, Zimmermann RC, Ferrero H, Shawber CJ, Kitajewski J, Simon C, Pellicer A, Gomez R. Delta-like ligand 4 regulates vascular endothelial growth factor receptor 2-driven luteal angiogenesis through induction of a tip/stalk phenotype in proliferating endothelial cells. Fertil Steril, 2013, 100: 1768–1776 e1761
Chang L, Noseda M, Higginson M, Ly M, Patenaude A, Fuller M, Kyle AH, Minchinton AI, Puri MC, Dumont DJ, Karsan A. Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. Proc Natl Acad Sci USA, 2012, 109: 6993–6998
Cappellari O, Benedetti S, Innocenzi A, Tedesco FS, Moreno-Fortuny A, Ugarte G, Lampugnani MG, Messina G, Cossu G. Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory. Dev Cell, 2013, 24: 586–599
Gridley T. Notch signaling in the vasculature. Curr Top Dev Biol, 2010, 92: 277–309
Hofmann JJ, Briot A, Enciso J, Zovein AC, Ren S, Zhang ZW, Radtke F, Simons M, Wang Y, Iruela-Arispe ML. Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome. Development, 2012, 139: 4449–4460
Yuan ZR, Kohsaka T, Ikegaya T, Suzuki T, Okano S, Abe J, Kobayashi N, Yamada M. Mutational analysis of the Jagged 1 gene in Alagille syndrome families. Hum Mol Genet, 1998, 7: 1363–1369
Liu H, Zhang W, Kennard S, Caldwell RB, Lilly B. Notch3 is critical for proper angiogenesis and mural cell investment. Circ Res, 2010, 107: 860–870
Wang Y, Pan L, Moens CB, Appel B. Notch3 establishes brain vascular integrity by regulating pericyte number. Development, 2014, 141: 307–317
Uyama E, Tokunaga M, Suenaga A, Kotorii S, Kamimura K, Takahashi K, Tabira T, Uchino M. Arg133Cys mutation of Notch3 in two unrelated Japanese families with CADASIL. Int Med (Tokyo, Japan), 2000, 39: 732–737
Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 1996, 383: 707–710
Joutel A. Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature. BioEssays, 2011, 33: 73–80
Opherk C, Duering M, Peters N, Karpinska A, Rosner S, Schneider E, Bader B, Giese A, Dichgans M. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet, 2009, 18: 2761–2767
Jin S, Hansson EM, Tikka S, Lanner F, Sahlgren C, Farnebo F, Baumann M, Kalimo H, Lendahl U. Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ Res, 2008, 102: 1483–1491
Scheppke L, Murphy EA, Zarpellon A, Hofmann JJ, Merkulova A, Shields DJ, Weis SM, Byzova TV, Ruggeri ZM, Iruela-Arispe ML, Cheresh DA. Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane. Blood, 2012, 119: 2149–2158
Liu H, Kennard S, Lilly B. NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res, 2009, 104: 466–475
Xia Y, Bhattacharyya A, Roszell EE, Sandig M, Mequanint K. The role of endothelial cell-bound Jagged1 in Notch3-induced human coronary artery smooth muscle cell differentiation. Biomaterials, 2012, 33: 2462–2472
Bentley K, Franco CA, Philippides A, Blanco R, Dierkes M, Gebala V, Stanchi F, Jones M, Aspalter IM, Cagna G, Westrom S, Claesson-Welsh L, Vestweber D, Gerhardt H. The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis. Nat Cell Biol, 2014, 16: 309–321
Lobov IB, Cheung E, Wudali R, Cao J, Halasz G, Wei Y, Economides A, Lin HC, Papadopoulos N, Yancopoulos GD, Wiegand SJ. The Dll4/Notch pathway controls postangiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow. Blood, 2011, 117: 6728–6737
Outtz HH, Tattersall IW, Kofler NM, Steinbach N, Kitajewski J. Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood, 2011, 118: 3436–3439
Hu J, Srivastava K, Wieland M, Runge A, Mogler C, Besemfelder E, Terhardt D, Vogel MJ, Cao L, Korn C, Bartels S, Thomas M, Augustin HG. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science, 2014, 343: 416–419
Brunt EM, Gouw AS, Hubscher SG, Tiniakos DG, Bedossa P, Burt AD, Callea F, Clouston AD, Dienes HP, Goodman ZD, Roberts EA, Roskams T, Terracciano L, Torbenson MS, Wanless IR. Pathology of the liver sinusoids. Histopathology, 2014, 64: 907–920
Wang L, Wang CM, Hou LH, Dou GR, Wang YC, Hu XB, He F, Feng F, Zhang HW, Liang YM, Dou KF, Han H. Disruption of the transcription factor recombination signal-binding protein-Jkappa (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice. Hepatology, 2009, 49: 268–277
Kume T. Ligand-dependent Notch signaling in vascular formation. Adv Exp Med Biol, 2012, 727: 210–222
De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiere B, Cauwenberghs S, Eelen G, Phng LK, Betz I, Tembuyser B, Brepoels K, Welti J, Geudens I, Segura I, Cruys B, Bifari F, Decimo I, Blanco R, Wyns S, Vangindertael J, Rocha S, Collins RT, Munck S, Daelemans D, Imamura H, Devlieger R, Rider M, Van Veldhoven PP, Schuit F, Bartrons R, Hofkens J, Fraisl P, Telang S, Deberardinis RJ, Schoonjans L, Vinckier S, Chesney J, Gerhardt H, Dewerchin M, Carmeliet P. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell, 2013, 154: 651–663
De Bock K, Georgiadou M, Carmeliet P. Role of endothelial cell metabolism in vessel sprouting. Cell Metab, 2013, 18: 634–647
Sawada N, Jiang A, Takizawa F, Safdar A, Manika A, Tesmenitsky Y, Kang KT, Bischoff J, Kalwa H, Sartoretto JL, Kamei Y, Benjamin LE, Watada H, Ogawa Y, Higashikuni Y, Kessinger CW, Jaffer FA, Michel T, Sata M, Croce K, Tanaka R, Arany Z. Endothelial PGC-1alpha mediates vascular dysfunction in diabetes. Cell Metab, 2014, 19: 246–258
Estrach S, Cailleteau L, Franco CA, Gerhardt H, Stefani C, Lemichez E, Gagnoux-Palacios L, Meneguzzi G, Mettouchi A. Laminin-binding integrins induce Dll4 expression and Notch signaling in endothelial cells. Circ Res, 2011, 109: 172–182
Stenzel D, Franco CA, Estrach S, Mettouchi A, Sauvaget D, Rosewell I, Schertel A, Armer H, Domogatskaya A, Rodin S, Tryggvason K, Collinson L, Sorokin L, Gerhardt H. Endothelial basement membrane limits tip cell formation by inducing Dll4/Notch signalling in vivo. EMBO Rep, 2011, 12: 1135–1143
Nicoli S, Knyphausen CP, Zhu LJ, Lakshmanan A, Lawson ND. miR-221 is required for endothelial tip cell behaviors during vascular development. Dev Cell, 2012, 22: 418–429
Biyashev D, Veliceasa D, Topczewski J, Topczewska JM, Mizgirev I, Vinokour E, Reddi AL, Licht JD, Revskoy SY, Volpert OV. miR-27b controls venous specification and tip cell fate. Blood, 2012, 119: 2679–2687
Fung E, Tang SM, Canner JP, Morishige K, Arboleda-Velasquez JF, Cardoso AA, Carlesso N, Aster JC, Aikawa M. Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation, 2007, 115: 2948–2956
Cai WX, Liang L, Wang L, Han JT, Zhu XX, Han H, Hu DH, Zhang P. Inhibition of Notch signaling leads to increased intracellular ROS by up-regulating Nox4 expression in primary HUVECs. Cell Immunol, 2014, 287: 129–135
Boopathy AV, Pendergrass KD, Che PL, Yoon YS, Davis ME. Oxidative stress-induced Notch1 signaling promotes cardiogenic gene expression in mesenchymal stem cells. Stem Cell Res Ther, 2013, 4: 43
Oh P, Lobry C, Gao J, Tikhonova A, Loizou E, Manent J, van Handel B, Ibrahim S, Greve J, Mikkola H, Artavanis-Tsakonas S, Aifantis I. In vivo mapping of notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell, 2013, 13: 190–204
Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest, 2000, 105: 597–605
Yuan ZR, Kobayashi N, Kohsaka T. Human Jagged 1 mutants cause liver defect in Alagille syndrome by overexpression of hepatocyte growth factor. J Mol Biol, 2006, 356: 559–568
Bauer RC, Laney AO, Smith R, Gerfen J, Morrissette JJ, Woyciechowski S, Garbarini J, Loomes KM, Krantz ID, Urban Z, Gelb BD, Goldmuntz E, Spinner NB. Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis. Hum Mutat, 2010, 31: 594–601
Liu ZJ, Tan Y, Beecham GW, Seo DM, Tian R, Li Y, Vazquez-Padron RI, Pericak-Vance M, Vance JM, Goldschmidt-Clermont PJ, Livingstone AS, Velazquez OC. Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis, 2012, 225: 296–303
Guarani V, Deflorian G, Franco CA, Kruger M, Phng LK, Bentley K, Toussaint L, Dequiedt F, Mostoslavsky R, Schmidt MH, Zimmermann B, Brandes RP, Mione M, Westphal CH, Braun T, Zeiher AM, Gerhardt H, Dimmeler S, Potente M. Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature, 2011, 473: 234–238
Fukuda D, Aikawa E, Swirski FK, Novobrantseva TI, Kotelianski V, Gorgun CZ, Chudnovskiy A, Yamazaki H, Croce K, Weissleder R, Aster JC, Hotamisligil GS, Yagita H, Aikawa M. Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proc Natl Acad Sci USA, 2012, 109: E1868–1877
Katoh M. Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (review). Int J Mol Med, 2013, 32: 763–767
Zhao XC, Dou GR, Wang L, Liang L, Tian DM, Cao XL, Qin HY, Wang CM, Zhang P, Han H. Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells. Neoplasia, 2013, 15: 815–825
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at link.springer.com
Contributed equally to this work
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Zhang, P., Yan, X., Chen, Y. et al. Notch signaling in blood vessels: from morphogenesis to homeostasis. Sci. China Life Sci. 57, 774–780 (2014). https://doi.org/10.1007/s11427-014-4716-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-014-4716-0