- Open Access
Novel insights into the differential functions of Notch ligands in vascular formation
© Kume; licensee BioMed Central Ltd. 2009
- Received: 19 August 2009
- Accepted: 16 November 2009
- Published: 16 November 2009
The Notch signaling pathway is a critical component of vascular formation and morphogenesis in both development and disease. Compelling evidence indicates that Notch signaling is required for the induction of arterial-cell fate during development and for the selection of endothelial tip and stalk cells during sprouting angiogenesis. In mammals, two of the four Notch receptors (Notch1 and Notch4) and three of the five Notch ligands (Jagged1, Dll1, and Dll4) are predominantly expressed in vascular endothelial cells and are important for many aspects of vascular biology. During arterial cell-fate selection and angiogenesis, the roles of Notch1 and Notch4 are thought to be similar, and the function of Dll4 is well-characterized. However, the molecular mechanisms that determine the functional similarities and differences of Notch ligands in vascular endothelial cells remain largely unknown; consequently, additional research is needed to elucidate the ligand-specific functions and mechanisms associated with Notch activation in the vascular endothelium. Results from recent studies indicate that Dll1 and Dll4 have distinct roles in the specification and maintenance of arterial cell identity, while Dll4 and Jagged1 have opposing functions in tip- and stalk-cell selection during sprouting angiogenesis. This review will focus on the newly discovered, distinct functions of several Notch ligands in the regulation of blood vessel formation and will provide perspectives for future research in the field.
- Vascular Endothelial Growth Factor
- Notch Signaling
- Notch Pathway
- Notch Receptor
- Notch Ligand
Notch signaling is evolutionarily conserved and critical for cell-fate determination, differentiation, and many other biological processes . The mammalian Notch signaling pathway is composed of four Notch receptors (Notch1-4) and five ligands (Jagged1 and 2 and Delta-like [Dll] 1, 3, and 4). All of the ligands are transmembrane-type proteins and, consequently, Notch signaling is often mediated by cell-cell interactions. Transmission generally occurs between neighboring cells that express high levels of either the receptor or the ligand, although receptor-ligand coexpression occurs in some cells, such as vascular endothelial cells. Over the last decade, numerous studies have demonstrated that Notch signaling is critically involved in vascular development and disease [2–6]. For example, Notch signaling is required for arterial cell-fate determination during embryonic development, and the Notch pathway controls both developmental and pathological angiogenesis by modulating the selection of endothelial tip and stalk cells in newly sprouting blood vessels. Regulation of the Notch pathway in blood vessels has been well characterized; however, the specific roles of each Notch ligand during vascular formation and morphogenesis are unknown. Recent studies provide insight into the distinct functions of Notch ligands in blood vessels, and this review summarizes the current understanding of how several ligands differentially activate Notch signaling in the vasculature.
Activation of Notch signaling through cell-cell interactions (trans-interactions) has been well characterized; however, Notch ligands also regulate the Notch pathway by binding to Notch receptors within the same cell (cis-interactions) [10, 11]. In general, trans-interactions between Notch ligands and receptors activate Notch signaling, whereas cis-interactions are believed to inhibit Notch signaling . The precise mechanisms that mediate Notch activation by the cis-interactions remain unclear, and further studies need to be performed .
Signaling pathways/factors that regulate Notch ligand expression in vascular endothelial and smooth muscle cells
Endothelial tip cell formation in sprouting angiogenesis
Dll4 (↓) Jagged1 (↑)
Tip cell and stalk cell selection
VEGF + FGF2
Ischemia-induced postnatal arteriogenesis
Smooth muscle cells
Smooth muscle cell maturation
Mammalian Notch receptors and ligands involved in vascular development and disease
Proper vascular development; Postnatal neovascularization
Maturation of vascular smooth muscle cells
Null mice show normal vascular development; Notch1; Notch4 mutant mice have severe vascular defects; Gain-of-function experiments show vascular abnormalities in development and postnatal life
Dispensable for arterial specification; Formation of hematopoietic stem cells from the aorta; Smooth muscle differentiation and maturation; Proangiogenic regulation
Maintenance of arterial identity; Arterial smooth muscle differentiation; Postnatal arteriogenesis
Arterial specification; Tip cell and stalk cell selection during sprouting angiogenesis; Regulation of tumor angiogenesis
Of the four Notch ligands (Jagged1, Jagged2, Dll1, and Dll4) that are expressed in arterial endothelial cells, Dll4 alone is expressed in the dorsal aorta of mice at embryonic day 8.5 (E8.5), and its expression is restricted to vascular endothelial cells ; thus, Dll4 is believed to be the ligand for Notch1 and Notch4 during early vascular development (Figure 3). Dll4 mutant mice display early embryonic lethality with impaired arterial specification and AVMs that appear in a genotype-dependent manner (i.e., the severity increases with the number of mutant alleles) [35–37]. These observations further emphasize the importance of maintaining proper Notch activity levels during vascular development. Foxc1 and Foxc2 transcription factors directly activate the Dll4 promoter in endothelial cells, and their induction of Dll4 expression is enhanced by VEGF, which suggests that Foxc1 and Foxc2 act upstream of Notch signaling during arterial-cell specification [22, 27].
Dll1 expression is detected in arterial endothelial cells at a later stage (E13.5) of mouse development  and continues to be restricted to arterial endothelial cells in adults . Dll1 is not critically involved in arterial-cell specification; however, analyses in hypomorphic and endothelial-specific Dll1 mutant mice indicate that Dll1 is required for the maintenance of arterial identity . Expression of the arterial marker ephrinB2 is reduced, and the venous marker COUP-TFII is upregulated, in endothelial-specific Dll1 mutant mice, despite Dll4 expression in the mutant endothelial cells ; thus, Dll4 appears to be essential for initiating the arterial program, whereas Dll1 is required to maintain arterial identity during embryonic development. In addition, Sorensen et al. have shown that Dll1-mediated Notch1 activation upregulates VEGF receptor 2 (VEGFR2) and its coreceptor, neuropilin-1, which suggests that Dll1 enhances the responsiveness of arterial endothelial cells to VEGF signaling. Thus, Dll4-mediated Notch signaling occurs downstream of VEGF during arterial specification, whereas Dll1-mediated Notch signaling acts upstream of VEGF to maintain arterial identity (Figures 3 and 4). Dll1 is also important for ischemia-induced postnatal arteriogenesis and the induction of ephrinB2 .
Jagged1 does not play a critical role in arterial development [39–41] but is required for the definitive hematopoietic program in the dorsal aorta. After arterial and venous endothelial cells differentiate, the ventral region of the dorsal aorta, located in the aorta-gonad-mesonephros (AGM) region of the mid-gestation mouse embryo (around E10-11), generates the first adult hematopoietic stem cells (HSCs). Notch4 is broadly expressed throughout the aortic endothelium of the AGM, whereas Notch1 expression is restricted to the ventral region of the dorsal aorta [40, 42]. Importantly, three Notch ligands (Jagged1, Jagged2, and Dll4) have distinctive expression patterns in the dorsal aorta of the AGM: Jagged1 and Notch1 expression overlap in the dorsal aorta, Jagged2 expression occurs in endothelial cells adjacent to Notch1-positive endothelial cells, and Dll4 is expressed in both Notch1-positive and Notch1-negative endothelial cells [40, 42]. Analyses in Jagged1 mutant mice indicate that Jagged1 is required for Notch1 activation during the induction of intra-embryonic definitive hematopoiesis in the AGM . Jagged2 and Dll4 expression in the AGM of Jagged1 mutant embryos is normal, and hematopoiesis is normal in Jagged2 mutant mice ; thus, the function of Jagged1 is distinct from Dll4 and Jagged2 activity during the hematopoietic program of the newly formed aorta (Figure 5).
Notch3 is predominantly expressed in the vascular smooth muscle of arteries and is not expressed in veins. Mutations in human NOTCH3 are associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder that causes stroke and dementia and is accompanied by the degeneration of vascular smooth muscle cells ; adult Notch3 mutant mice display a defect in the maturation of arterial smooth muscle cells . As noted above, Jagged1 mutant mice exhibit normal arterial development [39, 40], yet endothelial-specific Jagged1 mutants have impaired vascular smooth muscle differentiation . This observation indicates that Jagged1 expression in the arterial endothelium activates Notch in neighboring cells, and that this function is critical for smooth muscle cell differentiation. Jagged1 expression by endothelial cells induces mural cells (pericytes in the microvasculature or smooth muscle cells in larger vessels) to express Notch3 and Jagged1, which subsequently promotes and maintains the differentiation phenotype of mural cells , whereas platelet-derived growth factor (PDGF) and angiotensin II downregulate Notch3 and Jagged1 expression in vascular smooth muscle cells . Furthermore, a recent study found that expression of the arterial smooth muscle marker smoothelin is impaired in Dll1 mutant mice , and this decline has also been observed in Notch3-mutant arteries . Taken together, these findings suggest that Jagged1 and Dll1 are the primary ligands that regulate Notch3 activity during smooth-muscle differentiation and maturation (Figure 6).
The formation of new blood vessels, a process known as angiogenesis, involves the sprouting of endothelial cells. In response to VEGF stimulation, filopodia extend from a migratory endothelial cell at the vessel's tip (i.e., the tip cell), and proliferative endothelial cells (i.e., stalk cells) form the trunk of the new vessel. Recent studies in mice and zebrafish clearly demonstrate that Notch signaling interacts with VEGF signaling during tip-cell and stalk-cell specification . VEGF induces Dll4 expression in tip cells, then Dll4 activates the Notch pathway in adjacent endothelial cells to reduce expression of VEGFR2 and VEGFR3, thereby suppressing the tip-cell phenotype, and tip-cell phenotype suppression cell-autonomously promotes the stalk-cell phenotype. Together, these mechanisms balance tip-cell and stalk-cell selection and, consequently, limit the number of sprouting vessels (Figure 7). Genetic or pharmacological disruption of Dll4-Notch signaling leads to excessive tip-cell formation and vessel sprouting in cultured cells, in zebrafish and mouse embryos, and during tumor angiogenesis [23, 25, 46–51].
By using endothelial-specific Jagged1 mutant mice and mice that overexpress Jagged1 in vascular endothelial cells, Benedito et al. demonstrated that Jagged1 enhances angiogenesis and antagonizes the effects of Dll4-mediated Notch signaling during sprouting angiogenesis . Jagged1 is strongly expressed in stalk cells, whereas Dll4 is predominantly detected in tip cells , and the antagonistic interaction between Dll4 and Jagged1 in endothelial cells is mediated by the glycosyltransferase Fringe, which regulates the posttranslational modifications of Notch receptors in a ligand-dependent manner. Fringe enhances Notch activation in response to Delta-like ligands and reduces Notch activity in response to Jagged ligands ; consequently, Fringe increases Dll4-induced endothelial Notch signaling and reduces Notch signaling in response to Jagged1 . Jagged1 also appears to promote vascular sprouting by regulating VEGFR3 expression in tip cells . Taken together, these results illustrate the opposing effects of Dll4 and Jagged1 on sprouting angiogenesis.
Dll4 is expressed in tumor vasculature [26, 36, 53, 54], and as observed in studies of developmental angiogenesis, the blockade of Dll4-mediated Notch signaling (via systemic administration of Dll4-neutralizing antibodies [47, 48] and systemic or local administration of modified Dll4 proteins [47, 55]) increased tumor-vessel sprouting, which indicates that Dll4-Notch signaling is critical for tip- and stalk-cell selection during tumor angiogenesis. Remarkably, the inhibition of Dll4-Notch signaling increased neovascularization but impaired tumor growth, because the non-productive angiogenesis reduced tumor perfusion. Conversely, Dll4 activation of endothelial Notch signaling reduces tumor angiogenesis, but increases vessel diameter and perfusion, which enhances tumor growth [47, 56]. For these reasons, Dll4 is now recognized as a potential therapeutic target for tumor angiogenesis .
As described above, Jagged1 antagonizes Dll4 during sprouting angiogenesis , and overexpression of Jagged1 in tumor cells has been shown to enhance neovascularization and tumor growth ; however, the role of Jagged1 in pathological angiogenesis (including tumor angiogenesis) is not yet fully understood. Current findings suggest that angiogenic sprouting in the tumor is tightly controlled by positive and negative regulation of Jagged1 and Dll4 in both endothelial and non-endothelial cells. Recent studies have shown that a soluble form of Notch1 (Notch decoy) acts as an antagonist of ligand-dependent Notch signaling by (potentially) interfering with Dll1, Dll4, and Jagged1 [59, 60]. Importantly, the Notch decoy reduces tumor growth without increasing vessel growth, which suggests that the effects of the Notch decoy differ from those induced by Dll4 blockade. It is therefore likely that the proangiogenic function of Jagged1 in tumor cells and endothelial cells could also influence tumor angiogenesis.
Notch signaling is also required for angiogenesis in peripheral ischemia models [32, 38] (Table 2). Blood flow recovery and postnatal neovascularization in response to hind-limb ischemia are impaired in both global and endothelial-specific Notch1+/- mice, but not in Notch4-/- mice . Dll1 is strongly induced in arterial endothelial cells during ischemia-induced arteriogenesis, and Dll1+/- mice display reduced collateral-artery growth and impaired blood-flow recovery after hind-limb ischemia . Notch activation and ephrinB2 induction are not observed in the collateral arteries of Dll1+/- mice .
Studies performed in the past few years clearly demonstrate that the different Notch ligands have distinct functions in vascular development and disease. This understanding has prompted numerous investigations into the mechanisms by which Notch signaling is essential for multiple aspects of vascular biology. However, given that the effects of Notch pathway activation on endothelial cells are context-dependent , many questions remain to be answered. First, the upstream signaling pathways that control the expression of Notch ligands in blood vessels remain largely unknown; VEGF induces Dll4 expression in endothelial cells (Table 1), but Jagged1 is absent in tip cells where Dll4 is highly expressed, which suggests that the two ligands are regulated differently. Second, the selective activation of Notch in vascular endothelium remains unclear; for example, Notch signaling is not activated in arteries of Dll1 mutant mice, despite the presence of Jagged1 and Dll4 . Third, the role of non-canonical Notch ligands, such as microfibril-associated glycoprotein (MAGP)-2 , is poorly understood. MAGP-2 binds to Jagged1, Jagged2, Dll1, and Notch1 [61, 62], and is known to modulate Notch signaling in sprouting angiogenesis [63, 64], but the mechanistic basis for the function of MAGP-2 in ligand-dependent Notch activation has yet to be elucidated. Finally, given that Dll4 and Jagged1 have opposing effects on angiogenesis, experiments that specifically inhibit each ligand with selective neutralizing antibodies  may be important not only for understanding how Notch is activated in the vasculature, but also for the development of therapeutic strategies designed to control angiogenesis by targeting Notch signaling.
The author is an Associate Professor at Northwestern University School of Medicine, USA. He completed his postdoctoral training in the lab of Brigid Hogan at the Howard Hughes Medical Institute at Vanderbilt University Medical Center, USA. He graduated with a Ph.D. in Molecular and Cellular Biology from the University of Tokyo, Japan.
The author thanks W. Kevin Meisner, PhD, ELS, for editorial support. This work was supported by a NIH grant (RO1 HL074121) to TK.
- Bray SJ: Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006, 7: 678-689. 10.1038/nrm2009.View ArticlePubMedGoogle Scholar
- Alva JA, Iruela-Arispe ML: Notch signaling in vascular morphogenesis. Curr Opin Hematol. 2004, 11: 278-283. 10.1097/01.moh.0000130309.44976.ad.View ArticlePubMedGoogle Scholar
- Gridley T: Notch signaling in vascular development and physiology. Development. 2007, 134: 2709-2718. 10.1242/dev.004184.View ArticlePubMedGoogle Scholar
- Hofmann JJ, Iruela-Arispe ML: Notch signaling in blood vessels: who is talking to whom about what?. Circ Res. 2007, 100: 1556-1568. 10.1161/01.RES.0000266408.42939.e4.View ArticlePubMedGoogle Scholar
- Phng LK, Gerhardt H: Angiogenesis: a team effort coordinated by notch. Dev Cell. 2009, 16: 196-208. 10.1016/j.devcel.2009.01.015.View ArticlePubMedGoogle Scholar
- Roca C, Adams RH: Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 2007, 21: 2511-2524. 10.1101/gad.1589207.View ArticlePubMedGoogle Scholar
- Talora C, Campese AF, Bellavia D, Felli MP, Vacca A, Gulino A, Screpanti I: Notch signaling and diseases: an evolutionary journey from a simple beginning to complex outcomes. Biochim Biophys Acta. 2008, 1782: 489-497.View ArticlePubMedGoogle Scholar
- Komatsu H, Chao MY, Larkins-Ford J, Corkins ME, Somers GA, Tucey T, Dionne HM, White JQ, Wani K, Boxem M, Hart AC: OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development. PLoS Biol. 2008, 6: e196-10.1371/journal.pbio.0060196.PubMed CentralView ArticlePubMedGoogle Scholar
- Kopan R, Ilagan MX: The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009, 137: 216-233. 10.1016/j.cell.2009.03.045.PubMed CentralView ArticlePubMedGoogle Scholar
- Fiuza UM, Arias AM: Cell and molecular biology of Notch. J Endocrinol. 2007, 194: 459-474. 10.1677/JOE-07-0242.View ArticlePubMedGoogle Scholar
- Zolkiewska A: ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci. 2008, 65: 2056-2068. 10.1007/s00018-008-7586-4.PubMed CentralView ArticlePubMedGoogle Scholar
- D'Souza B, Miyamoto A, Weinmaster G: The many facets of Notch ligands. Oncogene. 2008, 27: 5148-5167. 10.1038/onc.2008.229.PubMed CentralView ArticlePubMedGoogle Scholar
- Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T: Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 2000, 14: 1343-1352.PubMed CentralPubMedGoogle Scholar
- Wu J, Bresnick EH: Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation. Mol Cell Biol. 2007, 27: 2411-2422. 10.1128/MCB.02152-06.PubMed CentralView ArticlePubMedGoogle Scholar
- Wu J, Iwata F, Grass JA, Osborne CS, Elnitski L, Fraser P, Ohneda O, Yamamoto M, Bresnick EH: Molecular determinants of NOTCH4 transcription in vascular endothelium. Mol Cell Biol. 2005, 25: 1458-1474. 10.1128/MCB.25.4.1458-1474.2005.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1172/JCI8047.PubMed CentralView ArticlePubMedGoogle Scholar
- Wu J, Bresnick EH: Bare rudiments of notch signaling: how receptor levels are regulated. Trends Biochem Sci. 2007, 32: 477-485. 10.1016/j.tibs.2007.09.002.View ArticlePubMedGoogle Scholar
- Beckers J, Clark A, Wunsch K, Hrabe De Angelis M, Gossler A: Expression of the mouse Delta1 gene during organogenesis and fetal development. Mech Dev. 1999, 84: 165-168. 10.1016/S0925-4773(99)00065-9.View ArticlePubMedGoogle Scholar
- Sorensen I, Adams RH, Gossler A: DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood. 2009, 113: 5680-5688. 10.1182/blood-2008-08-174508.View ArticlePubMedGoogle Scholar
- Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G: Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev. 2001, 108: 161-164. 10.1016/S0925-4773(01)00469-5.View ArticlePubMedGoogle Scholar
- 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. 10.1161/CIRCRESAHA.108.184846.PubMed CentralView ArticlePubMedGoogle Scholar
- Hayashi H, Kume T: Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells. PLoS ONE. 2008, 3: e2401-10.1371/journal.pone.0002401.PubMed CentralView ArticlePubMedGoogle Scholar
- 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, Kalén M, Gerhardt H, Betsholtz C: Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007, 445: 776-780. 10.1038/nature05571.View ArticlePubMedGoogle Scholar
- Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M: Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol. 2003, 23: 14-25. 10.1128/MCB.23.1.14-25.2003.PubMed CentralView ArticlePubMedGoogle Scholar
- Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ: Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci. 2007, 104: 3219-3224. 10.1073/pnas.0611206104.PubMed CentralView ArticlePubMedGoogle Scholar
- Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL: Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res. 2005, 65: 8690-8697. 10.1158/0008-5472.CAN-05-1208.View ArticlePubMedGoogle Scholar
- Seo S, Fujita H, Nakano A, Kang M, Duarte A, Kume T: The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev Biol. 2006, 294: 458-470. 10.1016/j.ydbio.2006.03.035.View ArticlePubMedGoogle Scholar
- Williams CK, Li JL, Murga M, Harris AL, Tosato G: Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood. 2006, 107: 931-939. 10.1182/blood-2005-03-1000.PubMed CentralView ArticlePubMedGoogle Scholar
- Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM: Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development. 2001, 128: 3675-3683.PubMedGoogle Scholar
- Lawson ND, Vogel AM, Weinstein BM: Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell. 2002, 3: 127-136. 10.1016/S1534-5807(02)00198-3.View ArticlePubMedGoogle Scholar
- Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK: Essential role of endothelial Notch1 in angiogenesis. Circulation. 2005, 111: 1826-1832. 10.1161/01.CIR.0000160870.93058.DD.PubMed CentralView ArticlePubMedGoogle Scholar
- Takeshita K, Satoh M, Ii M, Silver M, Limbourg FP, Mukai Y, Rikitake Y, Radtke F, Gridley T, Losordo DW, Liao JK: Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res. 2007, 100: 70-78. 10.1161/01.RES.0000254788.47304.6e.PubMed CentralView ArticlePubMedGoogle Scholar
- Uyttendaele H, Ho J, Rossant J, Kitajewski J: Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci. 2001, 98: 5643-5648. 10.1073/pnas.091584598.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 2005, 102: 9884-9889. 10.1073/pnas.0504391102.PubMed CentralView ArticlePubMedGoogle Scholar
- Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J: Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 2004, 18: 2474-2478. 10.1101/gad.1239004.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 2004, 101: 15949-15954. 10.1073/pnas.0407290101.PubMed CentralView ArticlePubMedGoogle Scholar
- Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T: Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 2004, 18: 2469-2473. 10.1101/gad.1239204.PubMed CentralView ArticlePubMedGoogle Scholar
- Limbourg A, Ploom M, Elligsen D, Sorensen I, Ziegelhoeffer T, Gossler A, Drexler H, Limbourg FP: Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res. 2007, 100: 363-371. 10.1161/01.RES.0000258174.77370.2c.View ArticlePubMedGoogle Scholar
- High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA: Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci. 2008, 105: 1955-1959. 10.1073/pnas.0709663105.PubMed CentralView ArticlePubMedGoogle Scholar
- Robert-Moreno A, Guiu J, Ruiz-Herguido C, Lopez ME, Ingles-Esteve J, Riera L, Tipping A, Enver T, Dzierzak E, Gridley T, Espinosa L, Bigas A: Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J. 2008, 27: 1886-1895. 10.1038/emboj.2008.113.PubMed CentralView ArticlePubMedGoogle Scholar
- Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, Gendron-Maguire M, Rand EB, Weinmaster G, Gridley T: Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet. 1999, 8: 723-730. 10.1093/hmg/8.5.723.View ArticlePubMedGoogle Scholar
- Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A: RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development. 2005, 132: 1117-1126. 10.1242/dev.01660.View ArticlePubMedGoogle Scholar
- Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssière 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. 10.1038/383707a0.View ArticlePubMedGoogle Scholar
- Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A: Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 2004, 18: 2730-2735. 10.1101/gad.308904.PubMed CentralView ArticlePubMedGoogle Scholar
- Campos AH, Wang W, Pollman MJ, Gibbons GH: Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ Res. 2002, 91: 999-1006. 10.1161/01.RES.0000044944.99984.25.View ArticlePubMedGoogle Scholar
- Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J: Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development. 2007, 134: 839-844. 10.1242/dev.003244.View ArticlePubMedGoogle Scholar
- Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G: Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006, 444: 1032-1037. 10.1038/nature05355.View ArticlePubMedGoogle Scholar
- 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. 10.1038/nature05313.View ArticlePubMedGoogle Scholar
- Sainson RC, Aoto J, Nakatsu MN, Holderfield M, Conn E, Koller E, Hughes CC: Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J. 2005, 19: 1027-1029.PubMedGoogle Scholar
- Siekmann AF, Lawson ND: Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature. 2007, 445: 781-784. 10.1038/nature05577.View ArticlePubMedGoogle Scholar
- 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. 2007, 104: 3225-3230. 10.1073/pnas.0611177104.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1016/j.cell.2009.03.025.View ArticlePubMedGoogle Scholar
- Hainaud P, Contreres JO, Villemain A, Liu LX, Plouet J, Tobelem G, Dupuy E: 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. 2006, 66: 8501-8510. 10.1158/0008-5472.CAN-05-4226.View ArticlePubMedGoogle Scholar
- Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D: Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation. 2001, 69: 135-144. 10.1046/j.1432-0436.2001.690207.x.View ArticlePubMedGoogle Scholar
- Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley EJ, Duarte A, Gill PS: Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood. 2007, 109: 4753-4760. 10.1182/blood-2006-12-063933.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1158/0008-5472.CAN-07-0969.View ArticlePubMedGoogle Scholar
- 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. 10.1038/nrc2130.View ArticlePubMedGoogle Scholar
- Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J, Wang CY: Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005, 8: 13-23. 10.1016/j.ccr.2005.06.004.View ArticlePubMedGoogle Scholar
- Dufraine J, Funahashi Y, Kitajewski J: Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 2008, 27: 5132-5137. 10.1038/onc.2008.227.PubMed CentralView ArticlePubMedGoogle Scholar
- Funahashi Y, Hernandez SL, Das I, Ahn A, Huang J, Vorontchikhina M, Sharma A, Kanamaru E, Borisenko V, Desilva DM, Suzuki A, Wang X, Shawber CJ, Kandel JJ, Yamashiro DJ, Kitajewski J: A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 2008, 68: 4727-4735. 10.1158/0008-5472.CAN-07-6499.PubMed CentralView ArticlePubMedGoogle Scholar
- Miyamoto A, Lau R, Hein PW, Shipley JM, Weinmaster G: Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation. J Biol Chem. 2006, 281: 10089-10097. 10.1074/jbc.M600298200.View ArticlePubMedGoogle Scholar
- Nehring LC, Miyamoto A, Hein PW, Weinmaster G, Shipley JM: The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface. J Biol Chem. 2005, 280: 20349-20355. 10.1074/jbc.M500273200.View ArticlePubMedGoogle Scholar
- Albig AR, Becenti DJ, Roy TG, Schiemann WP: Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells. Microvasc Res. 2008, 76: 7-14. 10.1016/j.mvr.2008.01.001.PubMed CentralView ArticlePubMedGoogle Scholar
- Albig AR, Roy TG, Becenti DJ, Schiemann WP: Transcriptome analysis of endothelial cell gene expression induced by growth on matrigel matrices: identification and characterization of MAGP-2 and lumican as novel regulators of angiogenesis. Angiogenesis. 2007, 10: 197-216. 10.1007/s10456-007-9075-z.View ArticlePubMedGoogle Scholar
- Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, Fitch-Bruhns M, Lazetic S, Park IK, Sato A, Satyal S, Wang X, Clarke MF, Lewicki J, Gurney A: DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009, 5: 168-177. 10.1016/j.stem.2009.05.019.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.