Abstract
Cerebral cavernous malformations (CCM) commonly known as cavernous hemangioma are associated with abnormally enlarged thin-walled blood vessels. As a result, these dilated capillaries are prone to leakage and result in hemorrhages. Clinically, such hemorrhages lead to severe headaches, focal neurological deficits, and epileptic seizures. CCM is caused by loss of function mutations in one of the three well-known CCM genes: Krev interaction trapped 1 (KRIT1), OSM, and programmed cell death 10 (PDCD10). Loss of CCM genes have been shown to be synergistically related to decreased Notch signaling and excessive angiogenesis. Despite recent evidences indicating that Notch signaling plays a pivotal role in regulating angiogenesis, the role of Notch in CCM development and progression is still not clear. Here, we provide an update literature review on the current knowledge of the structure of Notch receptor and its ligands, its relevance to angiogenesis and more precisely to CCM pathogenesis. In addition to reviewing the current literatures, this review will also focus on the cross talk between Delta-Notch and vascular endothelial growth factor (VEGF) signaling in angiogenesis and in CCM pathogenesis. Understanding the role of Notch signaling in CCM development and progression might help provide a better insight for novel anti-angiogenic therapies.
Similar content being viewed by others
References
Bachmann E, Krogh TN, Hojrup P, Skjodt K, Teisner B (1996) Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology. J Reprod Fertil 107(2):279–285
Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137(6):1124–1135
Boulday G, Rudini N, Maddaluno L, Blecon A, Arnould M, Gaudric A, Chapon F, Adams RH, Dejana E, Tournier-Lasserve E (2011) Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J Exp Med 208(9):1835–1847
Brutsch R, Liebler SS, Wustehube J, Bartol A, Herberich SE, Adam MG, Telzerow A, Augustin HG, Fischer A (2010) Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis. Circ Res 107(5):592–601
Cavalcanti DD, Kalani MY, Martirosyan NL, Eales J, Spetzler RF, Preul MC (2012) Cerebral cavernous malformations: from genes to proteins to disease. J Neurosurg 116(1):122–132
Chillakuri CR, Sheppard D, Lea SM, Handford PA (2012) Notch receptor-ligand binding and activation: insights from molecular studies. Semin Cell Dev Biol 23(4):421–428
Dejana E, Orsenigo F (2013) Endothelial adherens junctions at a glance. J Cell Sci 126(Pt 12):2545–2549
Dexter JS (1914) The analysis of a case of continuous variation in Drosophila by a study of its linkage relations. Am Nat 48:712–758
Dong X, Wang YS, Dou GR, Hou HY, Shi YY, Zhang R, Ma K, Wu L, Yao LB, Cai Y, Zhang J (2011) Influence of Dll4 via HIF-1alpha-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions. PLoS ONE 6(4):e18481
D’Souza B, Meloty-Kapella L, Weinmaster G (2010) Canonical and non-canonical Notch ligands. Curr Top Dev Biol 92:73–129
Ehebauer MT, Chirgadze DY, Hayward P, Martinez Arias A, Blundell TL (2005) High-resolution crystal structure of the human Notch 1 ankyrin domain. Biochem J 392(Pt 1):13–20
Eiraku M, Hirata Y, Takeshima H, Hirano T, Kengaku M (2002) Delta/notch-like epidermal growth factor (EGF)-related receptor, a novel EGF-like repeat-containing protein targeted to dendrites of developing and adult central nervous system neurons. J Biol Chem 277(28):25400–25407
Espinoza I, Pochampally R, Xing F, Watabe K, Miele L (2013) Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther 6:1249–1259
Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013) Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med 19(5):302–308
Fiuza UM, Arias AM (2007) Cell and molecular biology of Notch. J Endocrinol 194(3):459–474
Fukushima H, Nakao A, Okamoto F, Shin M, Kajiya H, Sakano S, Bigas A, Jimi E, Okabe K (2008) The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol 28(20):6402–6412
Gibson MA, Sandberg LB, Grosso LE, Cleary EG (1991) Complementary DNA cloning establishes microfibril-associated glycoprotein (MAGP) to be a discrete component of the elastin-associated microfibrils. J Biol Chem 266(12):7596–7601
Guruharsha KG, Kankel MW, Artavanis-Tsakonas S (2012) The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 13(9):654–666
Hainaud P, Contreres JO, Villemain A, Liu LX, Plouet J, Tobelem G, Dupuy E (2006) The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res 66(17):8501–8510
He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal 3(116):ra26
Heitzler P (2010) Biodiversity and noncanonical Notch signaling. Curr Top Dev Biol 92:457–481
Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445(7129):776–780
High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci U S A 105(6):1955–1959
Hill-Felberg S, Wu HH, Toms SA, Dehdashti AR (2015) Notch receptor expression in human brain arteriovenous malformations. J Cell Mol Med 19(8):1986–1993
Hodkinson PS, Elliott PA, Lad Y, McHugh BJ, MacKinnon AC, Haslett C, Sethi T (2007) Mammalian NOTCH-1 activates beta1 integrins via the small GTPase R-Ras. J Biol Chem 282(39):28991–29001
Hofmann JJ, Briot A, Enciso J, Zovein AC, Ren S, Zhang ZW, Radtke F, Simons M, Wang Y, Iruela-Arispe ML (2012) Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome. Development 139(23):4449–4460
Hwang J, Pallas DC (2014) STRIPAK complexes: structure, biological function, and involvement in human diseases. Int J Biochem Cell Biol 47:118–148
Jubb AM, Turley H, Moeller HC, Steers G, Han C, Li JL, Leek R, Tan EY, Singh B, Mortensen NJ, Noguera-Troise I, Pezzella F, Gatter KC, Thurston G, Fox SB, Harris AL (2009) Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. Br J Cancer 101(10):1749–1757
Kar S, Samii A, Bertalanffy H (2015) PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev 38(2):229–236, discussion 236–227
Kofler NM, Shawber CJ, Kangsamaksin T, Reed HO, Galatioto J, Kitajewski J (2011) Notch signaling in developmental and tumor angiogenesis. Genes Cancer 2(12):1106–1116
Krivtsov AV, Rozov FN, Zinovyeva MV, Hendrikx PJ, Jiang Y, Visser JW, Belyavsky AV (2007) Jedi—a novel transmembrane protein expressed in early hematopoietic cells. J Cell Biochem 101(3):767–784
Kuhnert F, Kirshner JR, Thurston G (2011) Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc Cell 3(1):20
Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6(3):237–244
Larrivee B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A (2012) ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell 22(3):489–500
Li Z, Wang J, Gong L, Wen Z, Xu C, Huang X (2011) Correlation of Delta-like ligand 4 (DLL4) with VEGF and HIF-1alpha expression in human glioma. Asian Pac J Cancer Prev 12(1):215–218
Limbourg A, Ploom M, Elligsen D, Sorensen I, Ziegelhoeffer T, Gossler A, Drexler H, Limbourg FP (2007) Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res 100(3):363–371
Liu H, Kennard S, Lilly B (2009) NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res 104(4):466–475
Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A 104(9):3219–3224
Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496
Meng H, Zhang X, Hankenson KD, Wang MM (2009) Thrombospondin 2 potentiates notch3/jagged1 signaling. J Biol Chem 284(12):7866–7874
Moriarity JL, Wetzel M, Clatterbuck RE, Javedan S, Sheppard JM, Hoenig-Rigamonti K, Crone NE, Breiter SN, Lee RR, Rigamonti D (1999) The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44(6):1166–1171, discussion 1172–1163
Murphy PA, Kim TN, Huang L, Nielsen CM, Lawton MT, Adams RH, Schaffer CB, Wang RA (2014) Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci U S A 111(50):18007–18012
Napp LC, Augustynik M, Paesler F, Krishnasamy K, Woiterski J, Limbourg A, Bauersachs J, Drexler H, Le Noble F, Limbourg FP (2012) Extrinsic Notch ligand Delta-like 1 regulates tip cell selection and vascular branching morphogenesis. Circ Res 110(4):530–535
Nichols JT, Miyamoto A, Olsen SL, D’Souza B, Yao C, Weinmaster G (2007) DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 176(4):445–458
Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037
Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL (2005) Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65(19):8690–8697
Poulos MG, Guo P, Kofler NM, Pinho S, Gutkin MC, Tikhonova A, Aifantis I, Frenette PS, Kitajewski J, Rafii S, Butler JM (2013) Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep 4(5):1022–1034
Rauen T, Raffetseder U, Frye BC, Djudjaj S, Muhlenberg PJ, Eitner F, Lendahl U, Bernhagen J, Dooley S, Mertens PR (2009) YB-1 acts as a ligand for Notch-3 receptors and modulates receptor activation. J Biol Chem 284(39):26928–26940
Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier-Lasserve E (2010) Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J 277(5):1070–1075
Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K (2002) The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 277(33):29399–29405
Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley EJ, Duarte A, Gill PS (2007) Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109(11):4753–4760
Schleider E, Stahl S, Wustehube J, Walter U, Fischer A, Felbor U (2011) Evidence for anti-angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3. Neurogenetics 12(1):83–86
Schmidt MH, Bicker F, Nikolic I, Meister J, Babuke T, Picuric S, Muller-Esterl W, Plate KH, Dikic I (2009) Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nat Cell Biol 11(7):873–880
Schneider H, Errede M, Ulrich NH, Virgintino D, Frei K, Bertalanffy H (2011) Impairment of tight junctions and glucose transport in endothelial cells of human cerebral cavernous malformations. J Neuropathol Exp Neurol 70(6):417–429
Schulz GB, Wieland E, Wustehube-Lausch J, Boulday G, Moll I, Tournier-Lasserve E, Fischer A (2015) Cerebral cavernous malformation-1 protein controls DLL4-Notch3 signaling between the endothelium and pericytes. Stroke 46(5):1337–1343
Shin HM, Minter LM, Cho OH, Gottipati S, Fauq AH, Golde TE, Sonenshein GE, Osborne BA (2006) Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J 25(1):129–138
Song LL, Peng Y, Yun J, Rizzo P, Chaturvedi V, Weijzen S, Kast WM, Stone PJ, Santos L, Loredo A, Lendahl U, Sonenshein G, Osborne B, Qin JZ, Pannuti A, Nickoloff BJ, Miele L (2008) Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 27(44):5833–5844
Sorensen I, Adams RH, Gossler A (2009) DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 113(22):5680–5688
Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A, Eichmann A (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci U S A 104(9):3225–3230
Tanriover G, Sozen B, Seker A, Kilic T, Gunel M, Demir N (2013) Ultrastructural analysis of vascular features in cerebral cavernous malformations. Clin Neurol Neurosurg 115(4):438–444
Teodorczyk M, Schmidt MH (2014) Notching on cancer’s door: notch signaling in brain tumors. Front Oncol 4:341
Whitehead KJ, Plummer NW, Adams JA, Marchuk DA, Li DY (2004) Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development 131(6):1437–1448
Wustehube J, Bartol A, Liebler SS, Brutsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A (2010) Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A 107(28):12640–12645
Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, Gendron-Maguire M, Rand EB, Weinmaster G, Gridley T (1999) Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8(5):723–730
Yao Y, Yao J, Radparvar M, Blazquez-Medela AM, Guihard PJ, Jumabay M, Bostrom KI (2013) Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency. Proc Natl Acad Sci U S A 110(47):19071–19076
You C, Sandalcioglu IE, Dammann P, Felbor U, Sure U, Zhu Y (2013) Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. J Cell Mol Med 17(3):407–418
Yu S, Sun J, Zhang J, Xu X, Li H, Shan B, Tian T, Wang H, Ma D, Ji C (2013) Aberrant expression and association of VEGF and Dll4/Notch pathway molecules under hypoxia in patients with lung cancer. Histol Histopathol 28(2):277–284
Zhu Y, Wu Q, Xu JF, Miller D, Sandalcioglu IE, Zhang JM, Sure U (2010) Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations. Neurosurg Focus 29(3):E1
Author information
Authors and Affiliations
Corresponding author
Additional information
Comments
Andreas Fischer, Heidelberg, Germany
Cerebral cavernous malformations (CCM) are slow-flow neurovascular lesions, which put patients at risk for developing intracranial hemorrhages, focal neurological deficits, and epileptic seizures. In the vast majority of familial CCM cases autosomal-dominantly inherited heterozygous inactivating mutations in three genes, CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10) can be found. It was assumed that a “second hit” in brain endothelial cells may lead to inactivation of the second allele. This biallelic loss of a CCM gene would then initiate lesion development (REFERENCE PMID: 19088123; PMID: 19088124). Therapeutic options for patients suffering from multiple lesions are very limited. Therefore, a better understanding of the CCM pathogenesis is essential to develop pharmaceutical interventions. However, we are still very far away from this ultimate goal. One needs to better understand the functions of the three CCM genes and in particular the signaling events downstream of CCM proteins (Rho kinase, MAPK, integrin activation, AKT, VEGF, Notch) to identify “druggable” targets.
In line with this notion, the review presented here by Dr. Kar and colleagues sheds light on the current knowledge of Notch and VEGF signaling downstream of CCM1–3 proteins. In several experimental settings using cultured endothelial cells or mice in which CCM1 or CCM3 was deleted specifically in endothelial cells, decreased activity of Notch signaling was observed (references are listed in the review article by Dr. Kar). Although the link from CCM proteins to Notch signaling activation is still a mystery, this observation may help to better understand the biology of CCMs. In the developing vasculature, Notch signaling gets dynamically upregulated and downregulated, and this alters the expression of VEGF receptors and the competence of endothelial cells to form a novel vessel sprout (REFERENCE PMID: 20871601). As such, impaired Notch signaling activity upon loss of CCM genes would strongly contribute to excessive vessel formation and impaired coverage of endothelial tubes with mural cells in CCMs.
However, several open questions remain. (1) It is still very difficult to determine the activation status of Notch signaling in human patient samples. Use of latest RNA sequencing techniques on the single cell level may help to resolve this in the near future. (2) It is still unknown how CCM proteins control Notch signaling. (3) The role of Notch signaling in the quiescent adult endothelium is very poorly understood. Interestingly, pharmacological blockade of Notch signaling with monoclonal DLL4 antibodies led to formation of benign vascular tumors (REFERENCE PMID: 20147986). This suggests that Notch signaling is needed to actively maintain a quiescent endothelium. (4) One needs to figure out how CCM genes are needed to keep endothelial cells in the adult brain in a resting state. There are inducible knockout mouse models for CCM1–3 available, which develop CCM-like lesion (REFERENCE PMID: 21859843; PMID: 23748444). Thus far, gene ablation was induced in the perinatal period in which the vasculature is still very active. Local inactivation of CCM genes in the adult brain will be better suited to mimic the human situation. Such an approach, together with careful monitoring of Notch activity in blood vessels, will be of utmost importance to definitely judge about the role of Notch signaling in CCM pathogenesis.
Rights and permissions
About this article
Cite this article
Kar, S., Baisantry, A., Nabavi, A. et al. Role of Delta-Notch signaling in cerebral cavernous malformations. Neurosurg Rev 39, 581–589 (2016). https://doi.org/10.1007/s10143-015-0699-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10143-015-0699-y