Published online before print February 13, 2003, doi: 10.1161/01.ATV.0000060892.81529.8F
© 2003 American Heart Association, Inc.
ATVB In Focus |
Notch Signaling in Vascular Development
From the Second Department of Internal Medicine (T.I.), Gunma University School of Medicine, Gunma 371-8511, Japan; Center for Cardiovascular Development (Y.H.), Department of Medicine, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex; and Institute for Genetic Medicine (L.K.), Department of Biochemistry and Molecular Biology, and Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles.
Correspondence to Larry Kedes, 2250 Alcazar Street, Los Angeles, CA 90089. E-mail kedes{at}hsc.usc.edu
Previous Brief Review in this Series:
Hillebrands J-L, Klatter FA, Rozing J. Origin of vascular smooth muscle cells and the role of circulating stem cells in transplant arteriosclerosis. 2003;23:380–387.
Abstract
Notch signaling is an extremely conserved and widely used mechanism regulating cell fate in metazoans. Interaction of Notch receptors (Notch) with their ligands (Delta-like or Jagged) leads to cleavage of the Notch intracellular domain (NICD) that migrates into the nucleus. In the nucleus, NICD associates with a transcription factor, RBP-Jk. The NICD-RBP-Jk complex, in turn, upregulates expression of primary target genes of Notch signaling, such as hairy and enhancer of split (HES) and HES-related repressor protein (HERP) transcriptional repressors. Recent evidence has demonstrated that the Notch pathway is involved in multiple aspects of vascular development, including proliferation, migration, smooth muscle differentiation, angiogenic processes, and arterial-venous differentiation. In this brief review, we focus on ligands, receptors, and target genes of Notch signaling in the vascular system and discuss (1) tissue distribution; (2) gain- and loss-of-function studies; and (3) the role of Notch components in human diseases involving the vascular system.
Key Words: notch signaling • smooth muscle differentiation • angiogenic processes • vascular system
Formation of the vascular system is one of the earliest and most important events during embryogenesis in mammals. During the early stages of vascular development, the de novo formation of blood vessels occurs from a dispersed population of mesodermally derived endothelial cell (EC) precursors, angioblasts. Angioblasts first differentiate and assemble into a reticulum of homogeneously sized primitive blood vessels, or the primary vascular plexus, in a process termed vasculogenesis. This primary vascular plexus is then remodeled by the process of angiogenesis, which involves sprouting, bridging, and intussusception, to generate both the large and small vessels of the mature vascular system. During angiogenesis, endothelial channels are covered by multiple layers of smooth muscle cells (SMCs) in large vessels and by single pericytes around small vessels to provide structural support and stability for the vascular walls. A number of different intercellular signaling pathways have been implicated in the control of vasculogenesis and angiogenesis. These pathways include the vascular endothelial growth factor (VEGF) pathway, the transforming growth factor-ß pathway, fibroblast growth factor pathway, platelet-derived growth factor pathway, the Angiopoietin/Tie receptor pathway, the ephrin/Eph receptor pathway, and many other pathways. Recent studies have added the Notch signaling pathway to this list.1–8
The evolutionarily conserved Notch signaling pathway controls cell fate in metazoans through local cell-cell interactions.9–11 Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis.12 In vertebrates, receptors, ligands, and other components of Notch signaling are expressed in various organs from all three germ lines, including vessels (Table 1). Mutations of Notch receptors and ligands in mice lead to abnormalities in many tissues, including the vascular system (Table 2). Human diseases, such as Alagille syndrome (AGS) and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which show abnormalities in the cardiovascular system, are caused by mutations of the Notch ligand Jagged-1 and the receptor Notch-3, respectively.13–15 Such findings clearly demonstrate a crucial role of the Notch pathway in vascular development.
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Interaction of Notch receptors (Notch 1 to 4) with their ligands (Delta like 1, -3, -4, Jagged-1 and -2) leads to cleavage of the transmembrane Notch receptor, giving rise to the Notch intracellular domain (NICD) that migrates into the nucleus (Figure 1).16,17 In the nucleus, NICD associates with a transcription factor, RBP-Jk (also known as CSL for CBF1/Su(H)/Lag-1)9–11,16,17 and activates transcription from the RBP-Jk DNA binding site. The NICD-RBP-Jk complex upregulates expression of primary target genes of Notch signaling, such as hairy and enhancer of split (HES)-1, -5, -7 and more recently isolated HES-related repressor protein (HERP)-1 to -3 in mammals.18,19 The HES and HERP families are basic helix-loop-helix-type transcriptional repressors and appear to act as Notch effectors by negatively regulating expression of downstream target genes (Figure 1).20–23 Thus, many ligands, receptors, and effectors are involved in this pathway.
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In this review, we focus on various ligands, receptors, and effectors of Notch signaling in the vascular system. Studies on tissue distribution of those components should provide clues as to which Notch components are crucial for vascular development. We next describe the vascular phenotypes of mice deficient for Notch components as well as other gain- and loss-of-function studies, the results of which delimit their functions in vascular development. In addition, we also discuss the effects of Notch pathway mutations in human diseases (AGS and CADASIL), which exhibit abnormalities in the vascular system.
Tissue Distribution of Notch Pathway Components
The vascular system comprises several different kinds of vessels classified into three groups—arteries, veins, and lymphatics—with separate subdivisions into large vessels, small vessels, and capillaries (Table 1). These vessels primarily consist of ECs, supporting cells (SMCs and pericytes), and surrounding matrix. A number of reports have described the tissue distribution of various Notch components and closely evaluated distribution in the vessels from several species, including human, rat, mouse, chicken, and zebrafish. We summarize these observations in Table 1. Although the expression level of Notch components is likely dynamic during development and therefore making it difficult to detect transient expression, the data suggest that of all the known Notch components, mainly three ligands (Dll-4, Jagged-1, and Jagged-2), three receptors (Notch-1, -3, and -4) and three effectors (HERP-1, -2, and -3) are involved in the vascular system. One key function of the Notch pathway is to determine the identity of distinct cell subpopulations from bipotential precursor cells, a process known as lateral specification or lateral inhibition (Figure 2).9–11 Such cell fate control activity of Notch is exemplified by determination of T lymphoid versus B lymphoid cells and pancreatic exocrine versus endocrine cells in mammals.24,25 Therefore, we proceed on the supposition that the Notch pathway might also contribute to establishing two distinct subpopulations at different steps of vasculogenesis and angiogenesis, such as (1) EC versus SMC/pericyte; (2) artery versus vein; (3) pulmonary versus systemic vessels; and (4) large vessels versus capillaries. We describe the tissue distribution of Notch components from this point of view. We also describe the expression of Notch components in cultured cells although they do not always precisely reflect events during in vivo differentiation.
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Notch signaling plays a critical role, in addition to normal animal development, in the pathological conditions of different tissues. Vascular injury experimentally caused by balloon for instance, results in altered gene expression of Notch signaling components. Such potential roles of Notch in vascular pathology are also discussed.
ECs or SMCs/Pericytes?
Expression of Dll-4, Notch-1, and Notch-4 seems to be limited to the EC layer, whereas that of Notch-3 and HERP-3 appear to be confined to the SMC layer (see Table 1). Only one report shows that Notch-1 is expressed in the aorta throughout the EC and the SMC layers.26 Although Jagged-1 is likely to be expressed in both EC and SMC layers (Table 1), several groups have reported that expression of Jagged-1 is observed only in the EC of some arteries (Table 1), pulmonary vessels,27 and portal and hepatic veins.28 One report showed that Jagged-2 is expressed in EC.29 In neural crest-derived Monc1 cells that can differentiate into smooth muscle cells, CHF1 (HERP-1) turns positive after induction of differentiation.30 Consistent with this, HERP-1 is expressed in an aortic smooth muscle-derived cell line and induced in it by ligand stimulation.31 Hesr1 (HERP-2) expression is observed in purified human capillaries by reverse transcription polymerase chain reaction (RT-PCR) and is induced during in vitro capillary-like network formation.32 HERP-2 is also expressed in an aortic smooth muscle-derived cell line and is also induced by ligand stimulation.31 Expression of Notch-1 through 3 is also detected in an aortic smooth muscle-derived cell line at least by RT-PCR.31 Taken together, Jagged-1 and Notch-3 may be the only ligand and receptor in the Notch pathway that play an important role in VSMC lineage whereas several ligands (Dll-4, Jagged-2) and receptors (Notch-1, -4) are involved only in EC lineage. Jagged-1 seems to be the only ligand that is expressed in both ECs and SMCs. In terms of target genes, HERP-1 and HERP-3 may be SMC-specific effectors in the vascular system whereas HERP-2 may play some role in both ECs and SMCs. By targeting one of several distinct Notch pathways, Notch signaling might contribute to defining EC and SMC cell populations.
Arteries or Veins?
Arteries and veins are morphologically, functionally, and molecularly very different. However, little is known about how this distinction is established during vascular development. The tissue distribution of Notch components leads us to speculate that the Notch pathway may play a crucial role in defining artery versus vein. Villa et al33 recently reported that Notch-1, Notch-3, Notch-4, Dll-4, Jagged-1, and Jagged-2 are all expressed in arteries but are not expressed in veins. Expression of DeltaC as well as Notch5, a Notch ligand and a receptor of zebrafish, is also restricted to the dorsal aorta.34,35 A putative Notch effector, gridlock (zebrafish homologue of HERP-1), is selectively expressed in the dorsal aorta, but not in the axial or cardinal veins.36 Thus, many Notch components show arterial specific expression. However, there are several exceptions for vascular distribution of the Notch components. Expression of Jagged-1 was observed in portal,28,37 hepatic,28 cardinal,38 and vitelline veins.39 Transcripts of Jagged-1 were also upregulated in human umbilical vein endothelial cells (HUVECs) exposed to fibrin.40 Expression of Notch receptors has also been found in some venous components: Notch-1 and Notch-2 in HUVECs,40 Notch-3 in veins in brain,41 and Notch-4 in the cardinal vein.42 Thus, although the tissue distribution of most Notch components and a further functional analysis of arterial differentiation (see below) strongly suggest its pivotal role in defining arteries, the possibility remains that the Notch pathway might also play some roles in venous development.
Pulmonary or Systemic Vessels?
Expression of Jagged-1 in the pulmonary artery has been well studied because AGS, which is caused by mutation of Jagged-1, shows major abnormalities in pulmonary arteries.14,15 Jagged-1 is expressed in the pulmonary artery and arterioles27,33,37,38,43,44 but not in capillaries,43 which is in agreement with the pulmonary phenotype of AGS (see below). Taichman et al27 have reported EC-specific expression of Jagged-1 as well as Notch-1 in the pulmonary vessels. Although Loomes et al26 reported that two other receptors, Notch-2 and Notch-3, are expressed in the pulmonary artery, Taichman et al27 concluded that Notch-2 and Notch-3 are diffusely expressed throughout the lung but not specifically in the vessels. HERP-3 is expressed in the pulmonary artery.45 Histological sections from heterozygous Hey2lacZ/+ (HERP-1) mice stained for expression of the lacZ reporter gene with the Xgal reaction showed strong staining in the pulmonary arteries.46 We also observed strong expression of HERP-1 and HERP-2 in the lungs of adult rats by Northern blot analysis (unpublished data). These findings, along with the phenotype of AGS, indicate that Notch signaling is also involved in the development of pulmonary vasculature.
Large Vessels or Capillaries?
There are only a few reports showing expression of Notch components in capillaries. Villa et al33 showed that Notch-4 is the only receptor and Dll-4 is the only ligand expressed in capillaries among all receptors and ligands they examined. Expression of Notch-4 was also observed in capillaries in lung.42 Notch-3 was shown to be expressed in pericytes of capillaries.41 Rat brain microvessel endothelial cells (RBE4) express Notch-1, -3, -4, and Jagged-1.47 An RT-PCR study by Henderson et al32 revealed that HERP-2 transcripts were detected in capillary-ECs prepared from adipose tissue. Further extensive studies are required to determine the precise tissue distribution of Notch components in capillaries because there appears to be a discrepancy in expression found in vivo and in vitro.
Expression After Vascular Injury
Lindner et al29 have studied expression of Jagged-1, Jagged-2, and Notch-1 through 4 before and after balloon catheter denudation of the rat carotid artery. The findings of these authors was limited to observations of only the inner face of the artery, not its cross section, because they used en face preparations for in situ hybridization. Although expression of only Jagged-1, Jagged-2 and Notch-1 was observed in intact ECs, all of the many other Notch components they examined in their study were strongly induced in injured ECs. Importantly, all the 6 Notch components they examined were strongly expressed in injured SMCs after denudation of ECs, which is in sharp contrast with normal SMCs, which express only Jagged-1 and Notch-3.33 In contrast with this report, Wang et al48 found that in SMC of rat carotid arteries transcripts (determined by RT-PCR) for Notch-1, -2, and -3 as well as HERP-1, -2, and -3 were coordinately downregulated after balloon injury. They extracted RNA from the artery after removing the layers of intima and adventitia, thereby they consider their result to reflect events in the SMC layer. The Lindner study29 did not compare expression levels in injured SMC with those in normal SMC, which may explain the discrepancies in these reports.
Specificity Among Ligands, Receptors, and Effectors
Based on their tissue distribution (Table 1), there might be a specific relation between Jagged-1-Notch-3-HERP-1/HERP-3 in SMCs, but direct evidence is lacking. Similarly, using an aortic smooth muscle-derived A10 cell line that expresses Notch-1, Notch-2, and Notch-3 transcripts, we reported that distinct ligands, Dll-1 and Jagged-1, induced transcripts of both HERP-1 and HERP-2.31 These experiments did not reveal any specific relation among Notch ligands, receptors, and effectors. However, it is clear that not all the Notch components are equally expressed in vascular tissues and, rather, only selected sets of Notch components are implicated in angiogenesis. Clarifying the relationships among ligands, receptors, and effectors is one of the key issues whose clarification is required to understand how the Notch pathway might be implicated in establishing different vessel types (eg, artery versus vein) and vascular cell types (ie, ECs versus SMCs).
Gain- and Loss-of-Function Studies
Phenotype of Knockout Mice
Mice homozygous for null mutations of several components of the Notch pathway, including Notch-1, Notch-1 plus Notch-4, and Jagged-1, resulted in embryonic lethality with vascular remodeling defects (Table 2).49,50 Vasculogenesis proceeded normally in these mutants whereas the next step, angiogenesis, was disrupted, suggesting that Notch signaling plays a more important role in angiogenesis. Although Notch-4-deficient mice were viable and fertile,49 embryos homozygous for double mutations of Notch-1 and Notch-4 displayed a more severe phenotype in angiogenesis than Notch-1 single mutant embryos.49 These findings suggest a more important role of Notch-1 than Notch-4, as well as their redundant function in angiogenesis. A lack of vascular morphogenesis in mice homozygous for a processing-deficient allele of Notch-1 also underscores its role in vascular development.51 Although no expression of Dll-1 and Notch-2 was detected in large vessels (Table 1), both Dll-1-deficient and Notch-2-hypomorphic mice embryos show hemorrhage,52,53 possibly resulting from poor development of vascular structures. In Notch2-hypomorphic mice, mutant kidney glomeruli lack the normal capillary tuft, and the hyaloid vasculature of the eye was also affected. Along with the observation that even Notch-2 was induced in injured arteries despite a lack of its expression in normal arteries,29 both Dll-1 and Notch-2 may thus be crucial factors in the vascular system, at least in a context-dependent manner. Recently it was reported that Hey2 (HERP-1)-deficient mice did not exhibit any overt vascular phenotype, such as aortic coarctation, seen in a grl (a homologue of HERP1) mutant of zebrafish, suggesting that unlike Zebrafish, HERP1 function might be compensated by other factors in the vascular system in mice,46,54 including, of course, other HERP isoforms. Finally, mutation of the presenilin1 gene, which is involved in the processing of Notch intracellular domain, produced a complex phenotype and showed intracranial hemorrhage, also supporting the idea that Notch pathway regulates vascular development.55,56 Whether arterial-venous differentiation is disrupted and whether functions of ECs and SMCs are affected in the mutant mice described above remain to be answered. Because other Notch components, such as Dll-4, HERP-2, and HERP-3, which might have a different/similar/redundant role, are also expressed in the vasculature, analyses of mice with targeted disruption of these genes are awaited.
Transgenic Mice
EC-specific expression of an activated form of Notch-4 driven by the flk1-promoter led to embryonic lethality with abnormal vessel structure and patterning,57 whose phenotype is similar to that seen in Notch-1- and Notch-1/Notch-4-deficient mice.49 The similar vascular phenotypes observed in both the transgenic (gain-of-function) and the knockout mice (loss-of-function) suggest that there may be a window of appropriate Notch expression levels for proper development of the embryonic vasculature. This study also suggested that the Notch pathway is essential at least in development of ECs. However, it is critical to be cautious in interpreting data involving the consequences of unregulated overexpression of the NICD because it can lead to a physiologically irrelevant result by interacting with other pathways and by inappropriately enhancing its own pathway.12
Notch in Arterial-Venous Differentiation
The role of the Notch pathway in arterial-venous differentiation has been studied elegantly in zebrafish. Zebrafish Notch5 (previously referred to as Notch-3) is expressed within the dorsal aorta (DA) but not in veins.35 EC-specific expression of an activated form of Notch5 can repress expression of a venous-specific marker, flt4. Embryos lacking Notch activity as a consequence of overexpression of a dominant negative form of XSu(H), the Xenopus homologue of RBP-Jk, also fail to express arterial-specific markers, such as ephrinB2a and Notch5, within the DA. In the zebrafish mutant mindbomb (mib), which displays hallmarks of the neurogenic phenotype typical of defective Notch signaling, expression of several arterial-specific markers, including Notch5, ephrinB2, and DeltaC, was disrupted whereas expression of some venous markers, such as flt4 and rtk5, appeared in the DA.35 Taken together, Notch signaling appears to be required for arterial-venous differentiation and repression of venous fate.
The gridlock mutation (grlm145), originally isolated in a large-scale chemical mutagenesis screen for developmental mutations of the zebrafish, shows selective disturbance of assembly of the aorta.36 The grl gene (HERP-1 homologue) is strongly expressed in the dorsal aorta but not in the axial vein (Table 1). The grlm145 mutation changes the stop codon to Gly and extends the protein by 44 amino acids at its carboxyl terminus, resulting in the phenotype. Injection of wild-type grl RNA in the mutant restores a normal phenotype,36 indicating that grlm145 is a loss-of-function mutation. More interestingly, gridlock is required for arterial-venous differentiation during embryonic vascular development.58 Reduction in grl by antisense oligonucleotides ablates regions of the artery and expands continuous regions of the vein whereas overexpression of grl diminishes the vein without increasing the artery. Taken together, these observations suggest that the normal action of grl is to repress venous fate rather than to instructively generate arteries. Although Zhong et al58 have reported that grl is downstream of Notch, Lawson et al35 suggested that grl does not function as a downstream target gene of Notch, at least in the vascular system. How grl regulates the process of arterial-venous differentiation and what ligands and receptors are upstream of grl are major issues to be addressed. In sharp contrast with the phenotype of the grl mutant, however, mice homozygous for a Hey2 (HERP-1) null mutation did not show any obvious abnormalities in the vascular system.46,54 Although the reasons for different phenotypes between the mutants of two species are unknown, a lack of mouse HERP-1 might be compensated by other factors that zebrafish do not have or, during evolution, mouse HERP-1 might have acquired other functions distinct from that of zebrafish.
Recent studies suggest a complex signaling cascade responsible for establishing arterial cell fate.59 ECs in zebrafish embryos lacking Shh (Sonic hedgehog) activity fail to undergo arterial differentiation, as defined by the expression of artery-specific markers, such as ephrinB2a, whereas injection of mRNA encoding Shh can induce ectopic vascular expression of ephrinB2a.60 Although embryos lacking Shh fail to express VEGF within their somites, exogenous addition of VEGF in the embryo can rescue vascular ephrinB2a expression. Furthermore, VEGF is unable to rescue arterial marker gene expression in embryos lacking Notch function whereas exogenous Notch activity can induce arterial differentiation in the absence of VEGF signaling. Such studies suggest that VEGF acts downstream of Shh and upstream of the Notch pathway to determine arterial cell fate.60 Mukouyama et al61 reported that in mice peripheral nerves provide a template that determines the organotypic pattern of blood vessel branching and arterial differentiation in the skin, via local secretion of VEGF from sensory nerve fibers, Schwann cells, or both. Although these studies suggest that VEGF induces arterial differentiation by linking Shh with Notch signaling, further investigation is required to clarify the precise mechanism of arterial-venous differentiation by VEGF since veins may also be exposed to similar levels of VEGF.
In Vitro Studies
In vitro experiments have also provided us insight on roles of the Notch pathway in vascular development. Some groups suggested a negative role of Notch signaling in angiogenesis whereas others proposed a positive role. Zimrin et al40 reported that expression of the Jagged-1 gene was induced in HUVECs exposed to fibrin, which induced circular structures of HUVECs in vitro. Interestingly, the addition of an antisense oligonucleotide to Jagged-1 enhanced invasion and tube formation during fibroblast growth factor-induced angiogenesis,40 suggesting that Jagged-1 negatively regulates this process. Maciag and colleagues29,62,63 used a secreted form of the extracellular domain of Jagged-1 (soluble Jagged-1) as a dominant-negative effector, although the physiological effects of soluble ligands are highly controversial. NIH3T3 cells stably expressing soluble Jagged-1 form chord-like structure, which is a critical component of lumen formation mediated by ECs and epithelial cells.63 In addition, intradermal injection of such cells into the flank of nude mice resulted in formation of tissue masses with prominent angiogenesis,63 suggesting a positive role of soluble Jagged-1 in angiogenesis. Because soluble Jagged-1 seems to act as a dominant negative,62 the transmembrane Jagged-1/Notch pathway may function to negatively control angiogenesis. Consistent with this notion, Leong et al64 recently reported that activated Notch-4 in EC in vivo may inhibit angiogenesis partly by promoting ß1-integrin-mediated adhesion to the underlying matrix. In contrast, expression of Jagged-1 or activated Notch-4/int3 in cultured brain ECs induced microvessel-like structures with morphological and biochemical properties similar to brain endothelial microvessels,47 which leads to conclusions opposite those described above. The soluble Jagged-1 protein described above inhibited cell-matrix interaction, focal adhesion formation, and cellular migration of NIH3T3 cells while increasing cell-cell contacts. These findings suggested that endogenous Jagged-1/Notch may act to maintain cell interaction with the matrix and to activate the migratory ability of cells, possibly by decreasing cell-cell contacts. The authors suggested that this function of Notch might be active in regenerating ECs and SMCs after vascular injury to facilitate their migration.29 However, one should be careful in interpreting such data because the function of Notch signaling is likely dependent on cell context and because the activity of the soluble ligand has not been studied in vascular-derived cells.
Expression of mouse CHF1 (HERP-1) was induced during differentiation of neural crest-derived Monc1 cells into vascular smooth muscle cells.30 Expression of mRNAs for both HERP-1 and HERP-2 was induced in cultured SMCs by stimulation of Notch ligands, such as Dll-1 and Jagged-1.31 Such studies suggest that HERPs may have a role in VSMC as Notch effectors. In EC, Hesr1 (HERP-2) mRNA expression was induced during EC tube formation, a well-characterized in vitro angiogenic process, and gain- and loss-of-function studies showed that Hesr1 (HERP-2) was involved in proliferation, migration, and network formation of ECs.32
Collectively, these findings from in vivo and in vitro studies indicate that the Notch pathway is involved in multiple aspects of vascular development, including in vitro proliferation and migration of ECs, smooth muscle differentiation and endothelial tube formation, as well as in vivo angiogenic processes and arterial-venous cell fate determination. Because loss- and gain-of-function studies in the Notch pathway sometimes appear to yield similar results and because comparable experiments designed for similar purposes exhibited opposite results, we should remain cautious about the interpretations of the findings. Nevertheless, it is likely to be true that Notch signaling has an essential role in vascular development.
Human Diseases
Alagille Syndrome (AGS)
AGS, first described in 1975,65 is an autosomal-dominant disorder characterized by neonatal jaundice and a paucity of intrahepatic bile ducts. Features that often accompany this syndrome include congenital heart defects; abnormal vertebrae and decreased interpediculate distance in the lumbar spine; retinal pigmentary changes and posterior embryotoxion; and a typical faces consisting of broad forehead, pointed mandible, deep-set eyes, and a bulbous tip of the nose. The disease has a wide range of expression, ranging from an apparently normal phenotype to severe cases.66 Some patients exhibited only cardiovascular defects, such as tetralogy of Fallot and pulmonic stenosis.67 In terms of congenital heart diseases seen in AGS, peripheral pulmonary stenosis is the most common defect, but other structural cardiovascular defects, such as tetralogy of Fallot, atrial and ventricular septal defects, pulmonic valve stenosis, and coarctation of the aorta, are also present.37 Mutations in the Jagged-1 gene at 20p12 have been identified in AGS patients.14,15 These are inactivating mutations, generally leading to premature truncation of the Jagged-1 protein. The AGS phenotypes are consistent with the tissue distribution of Jagged-1 in the cardiovascular system (Table 1). An extensive survey of the types and frequency of Jagged-1 mutations in AGS patients revealed that patients with large deletions encompassing the entire Jagged-1 gene had the same phenotype as patients with intragenic Jagged-1 mutations, suggesting that haploinsufficiency for the Jagged-1 gene was the primary cause of AGS.68,69 However, an animal model for AGS, or mice heterozygous for Jagged-1 null allele, exhibited only anterior chamber eye defects but did not exhibit other phenotypes associated with AGS in humans.50 Recently, a more representative mouse model of AGS was generated. Mice doubly heterozygous for the Jagged-1 null allele and a Notch-2 hypomorphic allele exhibited developmental abnormalities characteristic of AGS. They exhibited jaundice; growth retardation; impaired differentiation of intrahepatic bile ducts; and defects in heart, eye, and kidney development.44 Heart defects include narrowing of the pulmonary artery, atrial, and ventricular septal defects; right ventricular hypoplasia; and an overriding aorta that are reminiscent of tetralogy of Fallot.44 These results strongly suggest that the Notch-2 gene acts as a genetic modifier of Jagged-1 mutations in mice. However, the hypothesis that the Notch-2 allele may influence the phenotypes of AGS patients remains to be addressed.
Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
CADASIL is an inherited vascular dementia caused by mutations in Notch-3 on chromosome 19p13.13 Although the CADASIL mutations do not affect normal vascular development, they cause a defect in vessel homeostasis. The disorder most commonly manifests with transient or permanent ischemic strokes, which occur at a mean age of 45 years (range 27 to 65 years).70,71 Most of these strokes are classic lacunar infarcts that arise in the absence of hypertension or any other recognized vascular risk factors. Pathologically, the arteriopathy underlying the disorder is neither atherosclerotic nor amyloid.72–74 It involves a thickening of the vessel wall and narrowing of the lumen in the small arteries penetrating the white matter. In the thickened walls, vascular smooth muscle cells (VSMCs) degenerate, marked secondary fibrosis occurs, and granular osmophilic deposits (GOMs), detected by electron microscopy, accumulate in the basal membrane of VSMCs.72–75 GOMs have not been characterized biochemically, and their origin remains unsolved.73 VSMCs appear to progressively lose a part of their cytoplasm, leading to their destruction.73 That VSMCs are the major site of pathological changes seen in CADASIL is in full agreement with tissue distribution of Notch-3 in SMC (Table 1). Pathological changes, including destruction of VSMCs and the presence of GOMs, have also been found in SMCs of small arteries in muscle and skin biopsies in patients, indicating that CADASIL is a systemic vascular disease,72,73,75 although vascular complications appear to be limited to the brain for unknown reasons.76 More than 95% of CADASIL cases are the result of stereotypical missense point mutations within the epidermal growth factor-like repeats of Notch-3, leading to the addition or loss of a cysteine residue.13,77,78 As a result, instead of the normal even number of 6 cysteines, the mutated epidermal growth factor repeat contains an uneven number, either 5 or 7 cysteines. It is possible that the alteration from an even to an uneven number of cysteines affects the formation of sulfur bridges and, thereby, the three-dimensional structure of the extracellular part of Notch-3.79 In rare CADASIL cases, small deletion mutants and even a mutant not involving a cysteine residue have been reported.77,80 How such mutations cause CADASIL has been addressed as well. Notch-3 undergoes a proteolytic cleavage, leading to a 210-kDa extracellular fragment and a 97-kDa intracellular fragment. In CADASIL patients, a dramatic and selective accumulation of the 210-kDa Notch-3 cleavage product was observed at the cytoplasmic membrane of VSMC, in close proximity to, but not within, the GOM.41 The accumulated Notch extracellular fragment is readily detected by skin biopsy immunostaining with high sensitivity (96%) and high specificity (100%), which is considered useful for diagnosis.81 In an in vitro study, Notch-3 protein with the CADASIL mutations is normally expressed on the cell surface, suggesting that the mutations do not disrupt receptor maturation.82 Also, the ability of the CADASIL mutants to bind to Delta1 was not disrupted when compared with that of wild-type Notch-3.82 These results strongly suggest that CADASIL mutations act downstream of ligand binding, presumably through impaired clearance of the Notch-3 ectodomain from the cell surface. Wang et al83 have recently proposed that Notch-3 may play a role in VSMC survival by inducing c-FLIP, a primary inhibitor of the Fas ligand signaling pathway. Disturbances of the clearance of the Notch-3 extracellular fragment may lead to defective signaling in VSMC and even lead to their degradation.79
Conclusions and Future Directions
We have reviewed here the accumulated evidence that the Notch pathway is involved in multiple aspects of vascular development. Expression analyses revealed that the major components of the Notch pathway in the vascular system consist of three ligands (Dll-4, Jagged-1, and Jagged-2), three receptors (Notch-1, -3, and -4), and three target genes (HERP-1, -2, and -3; Table 1). Although some components are detected in veins and venous-derived cell lines, the major sites of their expression are arterial ECs and/or SMCs (Table 1), suggesting a central role in arterial differentiation. Indeed, the Notch pathway is essential for arterial-venous differentiation in zebrafish. Also, the bulk of data from in vivo and in vitro studies have demonstrated that the Notch pathway positively and negatively regulates vascular development, especially angiogenesis, as well as differentiation of ECs and SMCs.
However, our review also found a number of apparent inconsistencies and problems in these studies. The tissue distribution of specific Notch components is not always consistent with vascular phenotypes of mice deficient for them. For instance, Notch-4-deficient mice do not exhibit any obvious vascular phenotype despite strong Notch-4 expression in arterial ECs (Tables 1 and 2). Although expression of Dll-1 and Notch-2 has not been detected in vessels, targeted disruption of them in mice caused hemorrhage (Tables 1 and 2). Nor is the expression of Notch components after vascular injury, consistent with their expression in intact vascular systems. Recent studies in zebrafish have suggested a crucial role of the Notch pathway in arterial-venous differentiation. However, Hey2 (mouse homologue of grl)-deficient mice have no obvious vascular abnormalities. Such findings lead us to conclude that the involvement of Notch in vascular development is poorly understood and that there remain many issues to be addressed. Is there a specific relation between ligands, receptors, and target genes in the vascular system? Are there any other Notch components involved in the vascular system? What components function at what steps in what cells? How does the Notch pathway play a role in differentiation of ECs and/or SMCs? How does the Notch pathway regulate arterial-venous differentiation? Does Notch regulate vascular development positively or negatively? Does the Notch pathway really play no role in the development of veins? Does Notch play any role in vasculogenesis or angiogenesis in pathological situations such as neoplasm, inflammation, wound repair, diabetic retinopathy, and formation of collateral vessels in ischemic diseases?
Given that Notch has a significant role in vascular development, further understanding of Notch function in the vascular system, in combination with knowledge about other pathways in vascular development, might lead to development of new therapeutic and diagnostic strategies for Notch-related diseases and the plethora of serious diseases that involve de novo formation of blood vessels.
Acknowledgments
This work was supported in part by a grant from the National Heart Lung and Blood Institute (to L.K.) and from the AHA-Texas affiliate (to Y.H.).
Footnotes
Series Editor: Giulio Gabbiani
Received December 11, 2002; accepted January 23, 2003.
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 Y. Li, K. Takeshita, P.-Y. Liu, M. Satoh, N. Oyama, Y. Mukai, M. T. Chin, L. Krebs, M. I. Kotlikoff, F. Radtke, et al. Smooth Muscle Notch1 Mediates Neointimal Formation After Vascular Injury Circulation, May 26, 2009; 119(20): 2686 - 2692. [Abstract] [Full Text] [PDF]
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 M. L. Calicchio, T. Collins, and H. P. Kozakewich Identification of Signaling Systems in Proliferating and Involuting Phase Infantile Hemangiomas by Genome-Wide Transcriptional Profiling Am. J. Pathol., May 1, 2009; 174(5): 1638 - 1649. [Abstract] [Full Text] [PDF]
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 H. Meng, X. Zhang, K. D. Hankenson, and M. M. Wang Thrombospondin 2 Potentiates Notch3/Jagged1 Signaling J. Biol. Chem., March 20, 2009; 284(12): 7866 - 7874. [Abstract] [Full Text] [PDF]
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 D. J. Trombly, T. K. Woodruff, and K. E. Mayo Suppression of Notch Signaling in the Neonatal Mouse Ovary Decreases Primordial Follicle Formation Endocrinology, February 1, 2009; 150(2): 1014 - 1024. [Abstract] [Full Text] [PDF]
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 D. Morrow, S. Guha, C. Sweeney, Y. Birney, T. Walshe, C. O'Brien, D. Walls, E. M. Redmond, and P. A. Cahill Notch and Vascular Smooth Muscle Cell Phenotype Circ. Res., December 5, 2008; 103(12): 1370 - 1382. [Abstract] [Full Text] [PDF]
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T. Quillard, S. Coupel, F. Coulon, J. Fitau, M. Chatelais, M.C. Cuturi, E. Chiffoleau, and B. Charreau Impaired Notch4 Activity Elicits Endothelial Cell Activation and Apoptosis: Implication for Transplant Arteriosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2258 - 2265. [Abstract] [Full Text] [PDF]
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S. Urs, A. Roudabush, C. F. O'Neill, I. Pinz, I. Prudovsky, D. Kacer, Y. Tang, L. Liaw, and D. Small Soluble Forms of the Notch Ligands Delta1 and Jagged1 Promote in Vivo Tumorigenicity in NIH3T3 Fibroblasts with Distinct Phenotypes Am. J. Pathol., September 1, 2008; 173(3): 865 - 878. [Abstract] [Full Text] [PDF]
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 M. Segarra, C. K. Williams, M. d. l. L. Sierra, M. Bernardo, P. J. McCormick, D. Maric, C. Regino, P. Choyke, and G. Tosato Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth Blood, September 1, 2008; 112(5): 1904 - 1911. [Abstract] [Full Text] [PDF]
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 K. Niessen, Y. Fu, L. Chang, P. A. Hoodless, D. McFadden, and A. Karsan Slug is a direct Notch target required for initiation of cardiac cushion cellularization J. Cell Biol., July 28, 2008; 182(2): 315 - 325. [Abstract] [Full Text] [PDF]
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A. Zeoli, P. Dentelli, A. Rosso, G. Togliatto, A. Trombetta, L. Damiano, P. F. di Celle, L. Pegoraro, F. Altruda, and M. F. Brizzi Interleukin-3 promotes expansion of hemopoietic-derived CD45+ angiogenic cells and their arterial commitment via STAT5 activation Blood, July 15, 2008; 112(2): 350 - 361. [Abstract] [Full Text] [PDF]
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S.-M. Kwon, M. Eguchi, M. Wada, Y. Iwami, K. Hozumi, H. Iwaguro, H. Masuda, A. Kawamoto, and T. Asahara Specific Jagged-1 Signal From Bone Marrow Microenvironment Is Required for Endothelial Progenitor Cell Development for Neovascularization Circulation, July 8, 2008; 118(2): 157 - 165. [Abstract] [Full Text] [PDF]
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D. S. Weber A Novel Mechanism of Vascular Smooth Muscle Cell Regulation by Notch: Platelet-Derived Growth Factor Receptor-{beta} Expression? Circ. Res., June 20, 2008; 102(12): 1448 - 1450. [Full Text] [PDF]
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N. A. Gude, G. Emmanuel, W. Wu, C. T. Cottage, K. Fischer, P. Quijada, J. A. Muraski, R. Alvarez, M. Rubio, E. Schaefer, et al. Activation of Notch-Mediated Protective Signaling in the Myocardium Circ. Res., May 9, 2008; 102(9): 1025 - 1035. [Abstract] [Full Text] [PDF]
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Y. Tang, S. Urs, and L. Liaw Hairy-Related Transcription Factors Inhibit Notch-Induced Smooth Muscle {alpha}-Actin Expression by Interfering With Notch Intracellular Domain/CBF-1 Complex Interaction With the CBF-1-Binding Site Circ. Res., March 28, 2008; 102(6): 661 - 668. [Abstract] [Full Text] [PDF]
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 C. K. Williams, M. Segarra, M. De La Luz Sierra, R. C.A. Sainson, G. Tosato, and A. L. Harris Regulation of CXCR4 by the Notch Ligand Delta-like 4 in Endothelial Cells Cancer Res., March 15, 2008; 68(6): 1889 - 1895. [Abstract] [Full Text] [PDF]
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S. Kennard, H. Liu, and B. Lilly Transforming Growth Factor- (TGF- 1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression J. Biol. Chem., January 18, 2008; 283(3): 1324 - 1333. [Abstract] [Full Text] [PDF]
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 J. Beliakoff, J. Lee, H. Ueno, A. Aiyer, I. L. Weissman, G. S. Barsh, R. D. Cardiff, and Z. Sun The PIAS-Like Protein Zimp10 Is Essential for Embryonic Viability and Proper Vascular Development Mol. Cell. Biol., January 1, 2008; 28(1): 282 - 292. [Abstract] [Full Text] [PDF]
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J.-L. Li, R. C.A. Sainson, W. Shi, R. Leek, L. S. Harrington, M. Preusser, S. Biswas, H. Turley, E. Heikamp, J. A. Hainfellner, et al. Delta-like 4 Notch Ligand Regulates Tumor Angiogenesis, Improves Tumor Vascular Function, and Promotes Tumor Growth In vivo Cancer Res., December 1, 2007; 67(23): 11244 - 11253. [Abstract] [Full Text] [PDF]
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 M. A. Schaller, R. Neupane, B. D. Rudd, S. L. Kunkel, L. E. Kallal, P. Lincoln, J. B. Lowe, Y. Man, and N. W. Lukacs Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines J. Exp. Med., November 26, 2007; 204(12): 2925 - 2934. [Abstract] [Full Text] [PDF]
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 J. B.-D. Ponio, C. Wright-Crosnier, M.-T. Groyer-Picard, C. Driancourt, I. Beau, M. Hadchouel, and M. Meunier-Rotival Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: inhibitory effect on Notch signaling Hum. Mol. Genet., November 15, 2007; 16(22): 2683 - 2692. [Abstract] [Full Text] [PDF]
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 A. Proweller, A. C. Wright, D. Horng, L. Cheng, M. M. Lu, J. J. Lepore, W. S. Pear, and M. S. Parmacek Notch signaling in vascular smooth muscle cells is required to pattern the cerebral vasculature PNAS, October 9, 2007; 104(41): 16275 - 16280. [Abstract] [Full Text] [PDF]
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 M. Santos, R. S. Moura, S. Gonzaga, C. Nogueira-Silva, S. Ohlmeier, and J. Correia-Pinto Embryonic Essential Myosin Light Chain Regulates Fetal Lung Development in Rats Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 330 - 338. [Abstract] [Full Text] [PDF]
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 S. H. McKellar, D. J. Tester, M. Yagubyan, R. Majumdar, M. J. Ackerman, and T. M. Sundt III Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms J. Thorac. Cardiovasc. Surg., August 1, 2007; 134(2): 290 - 296. [Abstract] [Full Text] [PDF]
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 K. Niessen and A. Karsan Notch signaling in the developing cardiovascular system Am J Physiol Cell Physiol, July 1, 2007; 293(1): C1 - C11. [Abstract] [Full Text] [PDF]
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 E. Arciniegas, M. G. Frid, I. S. Douglas, and K. R. Stenmark Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L1 - L8. [Abstract] [Full Text] [PDF]
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J. J. Hofmann and M. L. Iruela-Arispe Notch Signaling in Blood Vessels: Who Is Talking to Whom About What? Circ. Res., June 8, 2007; 100(11): 1556 - 1568. [Abstract] [Full Text] [PDF]
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D. Morrow, J. P. Cullen, P. A. Cahill, and E. M. Redmond Cyclic Strain Regulates the Notch/CBF-1 Signaling Pathway in Endothelial Cells: Role in Angiogenic Activity Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1289 - 1296. [Abstract] [Full Text] [PDF]
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J. S. Scehnet, W. Jiang, S. Ram Kumar, V. Krasnoperov, A. Trindade, R. Benedito, D. Djokovic, C. Borges, E. J. Ley, A. Duarte, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion Blood, June 1, 2007; 109(11): 4753 - 4760. [Abstract] [Full Text] [PDF]
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 V. A Fitsanakis, G. Piccola, A. P. Marreilha dos Santos, J. L Aschner, and M. Aschner Putative proteins involved in manganese transport across the blood-brain barr 1ier Human and Experimental Toxicology, April 1, 2007; 26(4): 295 - 302. [Abstract] [PDF]
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N. M.S. van den Akker, D. G.M. Molin, P. P.W.M. Peters, S. Maas, L. J. Wisse, R. van Brempt, C. J. van Munsteren, M. M. Bartelings, R. E. Poelmann, P. Carmeliet, et al. Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform Circ. Res., March 30, 2007; 100(6): 842 - 849. [Abstract] [Full Text] [PDF]
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J. Wu and E. H. Bresnick Glucocorticoid and Growth Factor Synergism Requirement for Notch4 Chromatin Domain Activation Mol. Cell. Biol., March 15, 2007; 27(6): 2411 - 2422. [Abstract] [Full Text] [PDF]
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X. L. Aranguren, A. Luttun, C. Clavel, C. Moreno, G. Abizanda, M. A. Barajas, B. Pelacho, M. Uriz, M. Arana, A. Echavarri, et al. In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells Blood, March 15, 2007; 109(6): 2634 - 2642. [Abstract] [Full Text] [PDF]
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A. Limbourg, M. Ploom, D. Elligsen, I. Sorensen, T. Ziegelhoeffer, A. Gossler, H. Drexler, and F. P. Limbourg Notch Ligand Delta-Like 1 Is Essential for Postnatal Arteriogenesis Circ. Res., February 16, 2007; 100(3): 363 - 371. [Abstract] [Full Text] [PDF]
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L. Shan, J. C. Aster, J. Sklar, and M. E. Sunday Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L500 - L509. [Abstract] [Full Text] [PDF]
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C. Cayrol, C. Lacroix, C. Mathe, V. Ecochard, M. Ceribelli, E. Loreau, V. Lazar, P. Dessen, R. Mantovani, L. Aguilar, et al. The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes Blood, January 15, 2007; 109(2): 584 - 594. [Abstract] [Full Text] [PDF]
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K. Takeshita, M. Satoh, M. Ii, M. Silver, F. P. Limbourg, Y. Mukai, Y. Rikitake, F. Radtke, T. Gridley, D. W. Losordo, et al. Critical Role of Endothelial Notch1 Signaling in Postnatal Angiogenesis Circ. Res., January 5, 2007; 100(1): 70 - 78. [Abstract] [Full Text] [PDF]
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D. Morrow, C. Sweeney, Y. A. Birney, S. Guha, N. Collins, P. M. Cummins, R. Murphy, D. Walls, E. M. Redmond, and P. A. Cahill Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo Am J Physiol Cell Physiol, January 1, 2007; 292(1): C488 - C496. [Abstract] [Full Text] [PDF]
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T. Weng, Z. Chen, N. Jin, L. Gao, and L. Liu Gene expression profiling identifies regulatory pathways involved in the late stage of rat fetal lung development Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1027 - L1037. [Abstract] [Full Text] [PDF]
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 S. Chiba Concise Review: Notch Signaling in Stem Cell Systems Stem Cells, November 1, 2006; 24(11): 2437 - 2447. [Abstract] [Full Text] [PDF]
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H. Doi, T. Iso, H. Sato, M. Yamazaki, H. Matsui, T. Tanaka, I. Manabe, M. Arai, R. Nagai, and M. Kurabayashi Jagged1-selective Notch Signaling Induces Smooth Muscle Differentiation via a RBP-J{kappa}-dependent Pathway J. Biol. Chem., September 29, 2006; 281(39): 28555 - 28564. [Abstract] [Full Text] [PDF]
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 N. S. Patel, M. S. Dobbie, M. Rochester, G. Steers, R. Poulsom, K. Le Monnier, D. W. Cranston, J.-L. Li, and A. L. Harris Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer. Clin. Cancer Res., August 15, 2006; 12(16): 4836 - 4844. [Abstract] [Full Text] [PDF]
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H. Doi, T. Iso, M. Yamazaki, H. Akiyama, H. Kanai, H. Sato, K. Kawai-Kowase, T. Tanaka, T. Maeno, E.-i. Okamoto, et al. HERP1 Inhibits Myocardin-Induced Vascular Smooth Muscle Cell Differentiation by Interfering With SRF Binding to CArG Box Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2328 - 2334. [Abstract] [Full Text] [PDF]
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D. Morrow, A. Scheller, Y. A. Birney, C. Sweeney, S. Guha, P. M. Cummins, R. Murphy, D. Walls, E. M. Redmond, and P. A. Cahill Notch-mediated CBF-1/RBP-J{kappa}-dependent regulation of human vascular smooth muscle cell phenotype in vitro Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1188 - C1196. [Abstract] [Full Text] [PDF]
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N. S. Patel, J.-L. Li, D. Generali, R. Poulsom, D. W. Cranston, and A. L. Harris Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function Cancer Res., October 1, 2005; 65(19): 8690 - 8697. [Abstract] [Full Text] [PDF]
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 T Haritunians, T Chow, R P J De Lange, J T Nichols, D Ghavimi, N Dorrani, D M St Clair, G Weinmaster, and C Schanen Functional analysis of a recurrent missense mutation in Notch3 in CADASIL J. Neurol. Neurosurg. Psychiatry, September 1, 2005; 76(9): 1242 - 1248. [Abstract] [Full Text] [PDF]
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 T. Nagase, M. Nagase, K. Yoshimura, T. Fujita, and I. Koshima Angiogenesis within the developing mouse neural tube is dependent on sonic hedgehog signaling: possible roles of motor neurons Genes Cells, June 1, 2005; 10(6): 595 - 604. [Abstract] [Full Text] [PDF]
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K. Fujimori, K. Kadoyama, and Y. Urade Protein Kinase C Activates Human Lipocalin-type Prostaglandin D Synthase Gene Expression through De-repression of Notch-HES Signaling and Enhancement of AP-2{beta} Function in Brain-derived TE671 Cells J. Biol. Chem., May 6, 2005; 280(18): 18452 - 18461. [Abstract] [Full Text] [PDF]
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D. Morrow, C. Sweeney, Y. A. Birney, P. M. Cummins, D. Walls, E. M. Redmond, and P. A. Cahill Cyclic Strain Inhibits Notch Receptor Signaling in Vascular Smooth Muscle Cells In Vitro Circ. Res., March 18, 2005; 96(5): 567 - 575. [Abstract] [Full Text] [PDF]
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A. Proweller, W. S. Pear, and M. S. Parmacek Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation J. Biol. Chem., March 11, 2005; 280(10): 8994 - 9004. [Abstract] [Full Text] [PDF]
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J. Wu, F. Iwata, J. A. Grass, C. S. Osborne, L. Elnitski, P. Fraser, O. Ohneda, M. Yamamoto, and E. H. Bresnick Molecular Determinants of NOTCH4 Transcription in Vascular Endothelium Mol. Cell. Biol., February 15, 2005; 25(4): 1458 - 1474. [Abstract] [Full Text] [PDF]
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 K. B. Atkins, C. A. Northcott, S. W. Watts, and F. C. Brosius Effects of PPAR-{gamma} ligands on vascular smooth muscle marker expression in hypertensive and normal arteries Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H235 - H243. [Abstract] [Full Text] [PDF]
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B. K. Hadland, S. S. Huppert, J. Kanungo, Y. Xue, R. Jiang, T. Gridley, R. A. Conlon, A. M. Cheng, R. Kopan, and G. D. Longmore A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development Blood, November 15, 2004; 104(10): 3097 - 3105. [Abstract] [Full Text] [PDF]
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M. Noseda, L. Chang, G. McLean, J. E. Grim, B. E. Clurman, L. L. Smith, and A. Karsan Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21Cip1 Repression Mol. Cell. Biol., October 15, 2004; 24(20): 8813 - 8822. [Abstract] [Full Text] [PDF]
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J.-C. Tille and M.S. Pepper Hereditary Vascular Anomalies: New Insights Into Their Pathogenesis Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1578 - 1590. [Abstract] [Full Text] [PDF]
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 K. Good, R. Ciosk, J. Nance, A. Neves, R. J. Hill, and J. R. Priess The T-box transcription factors TBX-37 and TBX-38 link GLP-1/Notch signaling to mesoderm induction in C. elegans embryos Development, May 1, 2004; 131(9): 1967 - 1978. [Abstract] [Full Text] [PDF]
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Y. Morikawa and P. Cserjesi Extra-embryonic vasculature development is regulated by the transcription factor HAND1 Development, May 1, 2004; 131(9): 2195 - 2204. [Abstract] [Full Text] [PDF]
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M. Noseda, G. McLean, K. Niessen, L. Chang, I. Pollet, R. Montpetit, R. Shahidi, K. Dorovini-Zis, L. Li, B. Beckstead, et al. Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation Circ. Res., April 16, 2004; 94(7): 910 - 917. [Abstract] [Full Text] [PDF]
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