Translocation renal cell carcinoma (tRCC) is a rare, aggressive kidney cancer primarily occurring in children. They are genetically defined by translocations involving MiT/TFE gene family members TFE3 or TFEB. The biology underlying tRCC development remains poorly understood, partly due to the lack of representative experimental models. We utilized human kidney organoids, or tubuloids, to engineer a tRCC model by expressing one of the most common MiT/TFE fusions, SFPQ-TFE3. Fusion-expressing tubuloids adopt a tRCC-like phenotype and gene expression signature in vitro and grow as clear cell RCC upon xenotransplantation in mice. Genome-wide binding analysis suggests that SFPQ-TFE3 reprograms gene expression signatures by widespread, aberrant DNA binding. Combining these analyses with single-cell mRNA readouts reveals a derailed epithelial differentiation trajectory that is at the root of transformation toward tRCC. Our study demonstrates that SFPQ-TFE3 expression is sufficient to transform kidney epithelial cells into tRCC and defines the trajectories underlying malignant transformation.

Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN(KD)) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASN(KD) elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASN(KD) ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.

Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1AΔEC mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1AΔEC mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1AΔEC mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.

Glutamine synthetase, encoded by the gene GLUL , is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation.

Current anti-angiogenic therapies in malignant and ocular diseases target growth factor signaling in order to attenuate excessive vascular growth. Although initial responses are promising, overall therapeutic success is limited due to insufficient efficiency, tumor refractoriness and resistance. Emerging evidence suggests that diverse growth factor signaling pathways in endothelial cells (ECs) converge onto cellular metabolism, creating an attractive target for novel alternative anti-angiogenic therapies. Recent studies show that ECs rely on glycolysis for ATP and biomass synthesis, necessary for proliferation and migration, key processes of angiogenesis. In addition, fatty acid β-oxidation (FAO) is essential for de novo nucleotide synthesis during EC proliferation. Initial proof-of-evidence has been given that administration of pharmacological inhibitors of those metabolic pathways can be used to inhibit pathological angiogenesis in vivo. Deciphering the role of other metabolic pathways and exploring the therapeutic potential of blocking these pathways await further investigation.

HomeCirculation ResearchVol. 115, No. 2Endothelial Cell Differentiation by SOX17 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEndothelial Cell Differentiation by SOX17Promoting the Tip Cell or Stalking Its Neighbor Instead? Jermaine Goveia, Annalisa Zecchin, Francisco Morales Rodriguez, Stijn Moens, Peter Stapor and Peter Carmeliet Jermaine GoveiaJermaine Goveia From the Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium (J.G., A.Z., F.M.R., S.M., P.S., P.C.); and Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium (J.G., A.Z., F.M., S.M., P.S., P.C.). Search for more papers by this author , Annalisa ZecchinAnnalisa Zecchin From the Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium (J.G., A.Z., F.M.R., S.M., P.S., P.C.); and Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium (J.G., A.Z., F.M., S.M., P.S., P.C.). Search for more papers by this author , Francisco Morales RodriguezFrancisco Morales Rodriguez From the Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium (J.G., A.Z., F.M.R., S.M., P.S., P.C.); and Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium (J.G., A.Z., F.M., S.M., P.S., P.C.). Search for more papers by this author , Stijn MoensStijn Moens From the Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium (J.G., A.Z., F.M.R., S.M., P.S., P.C.); and Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium (J.G., A.Z., F.M., S.M., P.S., P.C.). Search for more papers by this author , Peter StaporPeter Stapor From the Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium (J.G., A.Z., F.M.R., S.M., P.S., P.C.); and Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium (J.G., A.Z., F.M., S.M., P.S., P.C.). Search for more papers by this author and Peter CarmelietPeter Carmeliet From the Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium (J.G., A.Z., F.M.R., S.M., P.S., P.C.); and Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium (J.G., A.Z., F.M., S.M., P.S., P.C.). Search for more papers by this author Originally published7 Jul 2014https://doi.org/10.1161/CIRCRESAHA.114.304234Circulation Research. 2014;115:205–207Vessel sprouting relies on the differentiation of endothelial cells (ECs) into a migratory tip cell leading at the forefront, proliferating stalk cells elongating the vessel stalk, and quiescent phalanx cells lining the perfused vessel.1 The tip versus stalk cell balance is under the control of vascular endothelial growth factor (VEGF) and Notch signaling, respectively.1 During recent years, the transcription factor SRY-related HMG box 17 (SOX17) has emerged as a regulator of arterial (at the expense of venous) EC specification, but its role in inducing the tip versus stalk EC behavior remained incompletely defined. In this issue of Circulation Research, Lee et al2 identified SOX17 as an inducer of the tip cell phenotype and showed that Notch signaling suppresses SOX17 levels to promote a stalk cell phenotype (Figure). However, using similar genetic mouse models, another recent study reported noncongruent findings.3 Can we explain these divergent interpretations and what are the possible implications of these results?Download figureDownload PowerPointFigure. Scheme illustrating the proposed models of the mechanism of Sox17 in vessel sprouting according to Lee et al.2 Sox17 plays a central role in the induction of tip cell differentiation. Expression of Sox17 in tip cells induces tip cell behavior, whereas Notch signaling downregulates Sox17 in endothelial cells to induce stalk cell specification. These results contradict with previous observations from Corada et al3 (discussed in insets) who report that Sox17 is a tip cell suppressor, upstream, not downstream, of Notch signaling. Red arrows indicate novel regulatory pathways dissected by Lee et al.2 Ang2 indicates angiopoietin-2; Dll4, Delta-like 4; ESM1, endothelial cell-specific molecule 1; NICD, Notch intracellular domain; and VEGFR2, vascular endothelial growth factor receptor 2. Article, see p 215Except for a brief period of embryonic vasculogenesis during which the primitive vascular plexus is established, tissues are vascularized by angiogenesis via formation of new vessel sprouts.4 VEGF and Notch are key orchestrators of the specification of ECs into migratory, sprout-guiding tip cells and proliferating, sprout-elongating stalk cells, respectively (Figure). VEGF, secreted by cells in response to hypoxia, induces tip cell formation and Delta-like 4 expression in ECs. Delta-like 4, a ligand of the Notch receptor, activates stalk cell–promoting Notch signaling in neighboring ECs to ensure that there is only a single tip cell followed by stalk cell neighbors.1 Intriguingly, tip and stalk cell phenotypes are fluidly interchangeable, and competition for the tip ensures that the most competitive EC leads the vessel sprout. Apart from VEGF and Notch, other genetic and even metabolic signals determine the tip versus stalk cell phenotype,1,5 but the nature of many of those signals still remains elusive. In this respect, the finding that SOX17 is a new signal orchestrating tip versus stalk cell behavior is exciting.Lee et al2 provide several lines of evidence that SOX17 induces tip cell function. First, they show SOX17 expression in ECs at the vascular front of angiogenic capillary plexuses, a finding that hints at a role in tip cell formation. Second, Sox17-silenced ECs have decreased expression of Delta-like 4, VEGF receptor 2, angiopoietin-2, Platelet derived growth factor B-B, and other genes associated with the tip cell phenotype. Third, silencing of Sox17 impairs EC migration, formation of lamellipodia, and other characteristic features of endothelial tip cells. Fourth, Sox17 deletion in ECs from embryonic day 8.5 in Tie2-Cre×Sox17GFP/fl mice results in lethal vessel defects. Furthermore, tamoxifen-induced deletion of Sox17 in ECs after birth in VE-cadherin-CreERT2×Sox17fl/fl mice reduced vascular plexus outgrowth, vessel branching, and tip cell formation. And finally, EC-specific Sox17 overexpression induced vascular hypersprouting in both embryonic and postnatal angiogenesis. Thus, Sox17 overexpression promotes ECs to adopt a tip cell phenotype, whereas conversely a lack of Sox17 promotes stalk cell differentiation.The SOX (SRY-related HMG box) family of proteins constitutes a group of 20 highly conserved transcription factors playing a pivotal role in the regulation of gene expression in various developmental processes. The group of SOX group F (SOXF) proteins, namely SOX7, SOX17 and SOX18, act in an overlapping manner to support the formation and integrity of the vascular system, as demonstrated by the severe cardiovascular defects displayed by knockout mouse embryos lacking either 1 (Sox7, Sox17) or 2 (Sox17 and Sox18) of these genes.6,7 The importance of SOX17 in inducing angiogenesis has also been highlighted in retinal and tumor angiogenesis.8,9 Interestingly, SOX transcription factors, including SOX17, interact with Notch signals to determine hemogenic and arterial specification of ECs.3,10 By using a combination of genetic and pharmacological loss- and gain-of-function approaches, Lee et al2 demonstrate that Notch suppresses SOX17 levels in ECs to promote a stalk cell phenotype.Although these exciting insights advance our understanding of the fundamental mechanisms of vessel sprouting, they also introduce another level of complexity in the proposed model of SOX17 vascular regulation. Another recent study by Corada et al3 reported that SOX17 is an upstream, not downstream, regulator of Notch signaling in arterial differentiation. Furthermore, this group observed a vascular hypersprouting, not hyposprouting, phenotype upon SOX17 deletion in ECs. How can these apparently contradictory findings be reconciled? Although the precise underlying causes remain to be identified, some hypothetical reasons are discussed. First, both groups used exactly the same genetically engineered knockout mouse models, thus excluding the possibility that a different sort of genetic manipulation caused the divergence. Nonetheless, slight alterations in genetic backgrounds of the transgenic models used could affect the phenotype.Second, the postnatal mouse retina model of angiogenesis is a dynamic model, and EC branching, plexus outgrowth, and arteriovenous differentiation occur in a short timeframe. Therefore, differences in tamoxifen administration schemes used by both groups (administration route, dose, and duration) possibly evoked differences in recombination efficiency and vessel remodeling dynamics. At least from a theoretical perspective, a deletion of a proangiogenic gene in only a fraction of ECs might initially impair vessel outgrowth, but resultant ischemia because of hypoperfusion might lead to vessel overgrowth by nonrecombined wild-type ECs in an effort to compensate for the vascular defect. Compensation by nontransgenic ECs has been previously shown to rescue vascular defects by mutant ECs with a competitive angiogenic disadvantage.11 Documenting the in situ recombination efficiency of ECs in a particular vascular bed might thus aid to understand the phenotype under investigation.Another discrepancy is the relationship between Notch and SOX17. Lee et al2 provide evidence that Notch signaling downregulates SOX17 expression at the post-transcriptional level to promote a stalk cell phenotype, whereas Corada et al3 report that Notch signaling is regulated by SOX17 (Figure). Although these divergent findings require further reconciliation, it is noteworthy that SOX transcription factor function is dependent on the formation of complexes with interacting partners. Thus, the type and level of activity of SOX factors might theoretically vary depending on the availability and the sort of its binding partners in distinct EC subtypes. Also, the levels of SOX17 might influence its association with additional or other types of partners. Nevertheless, beyond the apparent contradictions and contextual effects of SOX17, the findings by Lee et al2 and Corada et al3 seem to direct toward an intriguing model that defines SOX17 as an integral part of Notch signaling in the vascular biology governing EC specification.The findings by Lee et al2 and Corada et al3 also raise several outstanding questions. For instance, if SOX17 is a bona fide tip cell signal, is it then also capable of ensuring the competitiveness of ECs to reach the tip position in mosaic cell–cell competition assays in vitro and more importantly in vivo, as used in previous studies?12 SOX17 is preferentially expressed in arterial ECs, and silencing of SOX17 not only favors venous at the expense of arterial EC specification but also stimulates increased tip cell formation.3 Given that ECs are generally thought to sprout from veins, does this imply that deficiency of SOX17 then promote formation of tip cells after prior differentiation to venous subtypes? How are SOX17’s context-dependent functions regulated, such as arterial differentiation and tip–stalk cell differentiation? Which other transcriptional cofactors are involved and how are they regulated? Which signals upregulate SOX17 levels in tip cells? How does the interplay between Notch and SOX17 affect the dynamic process of tip and stalk cell differentiation?Another outstanding question is whether SOX17 can become a target for angiogenic therapy and, if so, whether SOX17 should be blocked or activated to inhibit pathological angiogenesis. A previous study reported that EC-specific deficiency of SOX17 reduces vessel density while inducing vessel normalization in models of melanoma and lung cancer.8 These findings would lend support for the strategy to block SOX17 for inhibiting tumor angiogenesis. However, answering more conclusively the question whether SOX17 should be inhibited or stimulated to block pathological angiogenesis will require a better understanding of the contextual role of SOX17 in tip versus stalk cell–driven angiogenesis.Sources of FundingJ. Goveia is a PhD student supported by a Bijzonder onderzoeksfond (BOF) fellowship from the University of Leuven. S. Moens is supported by an Emmanuel Vanderschueren fellowship from the Flemish Association against Cancer (VLK). The work of P. Carmeliet is supported by a Federal Government Belgium grant (IUAP P7/03), long-term structural Methusalem funding by the Flemish Government, grants from the Research Foundation Flanders (FWO), the Foundation of Leducq Transatlantic Network (ARTEMIS), Foundation against cancer, an European Research Council (ERC) Advanced Research Grant (EU-ERC269073), and the AXA Research Fund.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Peter Carmeliet, MD, PhD, Vesalius Research Center, VIB, KU Leuven, Campus Gasthuisberg, Herestraat 49-B912, Leuven B-3000, Belgium. E-mail [email protected]References1. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis.Cell. 2011; 146:873–887.CrossrefMedlineGoogle Scholar2. Lee SH, Lee S, Yang H, Song S, Kim K, Saunders TL, Yoon JK, Koh GY, Kim I. Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.Circ Res. 2014; 115:215–226.LinkGoogle Scholar3. Corada M, Orsenigo F, Morini MF, Pitulescu ME, Bhat G, Nyqvist D, Breviario F, Conti V, Briot A, Iruela-Arispe ML, Adams RH, Dejana E. Sox17 is indispensable for acquisition and maintenance of arterial identity.Nat Commun. 2013; 4:2609.CrossrefMedlineGoogle Scholar4. Eichmann A, Yuan L, Moyon D, Lenoble F, Pardanaud L, Breant C. Vascular development: from precursor cells to branched arterial and venous networks.Int J Dev Biol. 2005; 49:259–267.CrossrefMedlineGoogle Scholar5. De Bock K, Georgiadou M, Carmeliet P. Role of endothelial cell metabolism in vessel sprouting.Cell Metab. 2013; 18:634–647.CrossrefMedlineGoogle Scholar6. Wat MJ, Beck TF, Hernández-García A, et al. Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1.Hum Mol Genet. 2012; 21:4115–4125.CrossrefMedlineGoogle Scholar7. Sakamoto Y, Hara K, Kanai-Azuma M, Matsui T, Miura Y, Tsunekawa N, Kurohmaru M, Saijoh Y, Koopman P, Kanai Y. Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos.Biochem Biophys Res Commun. 2007; 360:539–544.CrossrefMedlineGoogle Scholar8. Yang H, Lee S, Lee S, Kim K, Yang Y, Kim JH, Adams RH, Wells JM, Morrison SJ, Koh GY, Kim I. Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice.J Clin Invest. 2013; 123:418–431.CrossrefMedlineGoogle Scholar9. Ye X, Wang Y, Cahill H, Yu M, Badea TC, Smallwood PM, Peachey NS, Nathans J. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization.Cell. 2009; 139:285–298.CrossrefMedlineGoogle Scholar10. Clarke RL, Yzaguirre AD, Yashiro-Ohtani Y, Bondue A, Blanpain C, Pear WS, Speck NA, Keller G. The expression of Sox17 identifies and regulates haemogenic endothelium.Nat Cell Biol. 2013; 15:502–510.CrossrefMedlineGoogle Scholar11. Schoors S, Cantelmo AR, Georgiadou M, Stapor P, Wang X, Quaegebeur A, Cauwenberghs S, Wong BW, Bifari F, Decimo I, Schoonjans L, De Bock K, Dewerchin M, Carmeliet P. Incomplete and transitory decrease of glycolysis: a new paradigm for anti-angiogenic therapy?Cell Cycle. 2014; 13:16–22.CrossrefMedlineGoogle Scholar12. De Bock K, Georgiadou M, Schoors S, et al. Role of PFKFB3-driven glycolysis in vessel sprouting.Cell. 2013; 154:651–663.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Guo Y, Mei F, Huang Y, Ma S, Wei Y, Zhang X, Xu M, He Y, Heng B, Chen L and Deng X (2022) Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis, Bioactive Materials, 10.1016/j.bioactmat.2021.05.033, 7, (364-376), Online publication date: 1-Jan-2022. Guo Y, Ma S, Xu M, Wei Y, Zhang X, Huang Y, He Y, Heng B, Chen L and Deng X (2021) HtrA3‐Mediated Endothelial Cell–Extracellular Matrix Crosstalk Regulates Tip Cell Specification, Advanced Functional Materials, 10.1002/adfm.202100633, 31:30, (2100633), Online publication date: 1-Jul-2021. Lee J, Hur J, Kwon Y, Chae C, Choi J, Hwang I, Yun J, Kang J, Choi Y, Kim Y, Lee S, Lee C, Jo D, Seok H, Cho B, Baek S and Kim H (2021) KAI1(CD82) is a key molecule to control angiogenesis and switch angiogenic milieu to quiescent state, Journal of Hematology & Oncology, 10.1186/s13045-021-01147-6, 14:1, Online publication date: 1-Dec-2021. Southgate L, Machado R, Gräf S and Morrell N (2019) Molecular genetic framework underlying pulmonary arterial hypertension, Nature Reviews Cardiology, 10.1038/s41569-019-0242-x, 17:2, (85-95), Online publication date: 1-Feb-2020. Tao J, Han Q, Zhou H and Diao X (2019) Transcriptomic responses of regenerating earthworms (Eisenia foetida) to retinoic acid reveals the role of pluripotency genes, Chemosphere, 10.1016/j.chemosphere.2019.03.111, 226, (47-59), Online publication date: 1-Jul-2019. Liang T, Jia Y, Zhang R, Du Q and Chang Z (2018) Identification, molecular characterization and analysis of the expression pattern of $${\varvec{SoxF}}$$ SoxF subgroup genes the Yellow River carp, $${\varvec{Cyprinus} \varvec{carpio}}$$ Cyprinus carpio, Journal of Genetics, 10.1007/s12041-018-0898-8, 97:1, (157-172), Online publication date: 1-Mar-2018. Aspalter I, Gordon E, Dubrac A, Ragab A, Narloch J, Vizán P, Geudens I, Collins R, Franco C, Abrahams C, Thurston G, Fruttiger M, Rosewell I, Eichmann A and Gerhardt H (2015) Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch, Nature Communications, 10.1038/ncomms8264, 6:1, Online publication date: 1-Nov-2015. Iturriaga-Goyon E, Buentello-Volante B, Magaña-Guerrero F and Garfias Y (2021) Future Perspectives of Therapeutic, Diagnostic and Prognostic Aptamers in Eye Pathological Angiogenesis, Cells, 10.3390/cells10061455, 10:6, (1455) He Y, Tacconi C, Dieterich L, Kim J, Restivo G, Gousopoulos E, Lindenblatt N, Levesque M, Claassen M and Detmar M (2022) Novel Blood Vascular Endothelial Subtype-Specific Markers in Human Skin Unearthed by Single-Cell Transcriptomic Profiling, Cells, 10.3390/cells11071111, 11:7, (1111) July 7, 2014Vol 115, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.114.304234PMID: 24989487 Originally publishedJuly 7, 2014 KeywordsEditorialsreceptors, NotchPDF download Advertisement SubjectsAngiogenesisDevelopmental BiologyVascular Biology

Vessel sprouting relies on the differentiation of endothelial cells (ECs) into a migratory tip cell leading at the forefront, proliferating stalk cells elongating the vessel stalk, and quiescent phalanx cells lining the perfused vessel.1 The tip versus stalk cell balance is under the control of vascular endothelial growth factor (VEGF) and Notch signaling, respectively.1 During recent years, the transcription factor SRY-related HMG box 17 (SOX17) has emerged as a regulator of arterial (at the expense of venous) EC specification, but its role in inducing the tip versus stalk EC behavior remained incompletely defined. In this issue of Circulation Research , Lee et al2 identified SOX17 as an inducer of the tip cell phenotype and showed that Notch signaling suppresses SOX17 levels to promote a stalk cell phenotype (Figure). However, using similar genetic mouse models, another recent study reported noncongruent findings.3 Can we explain these divergent interpretations and what are the possible implications of these results? Figure. Scheme illustrating the proposed models of the mechanism of Sox17 in vessel sprouting according to Lee et al.2 Sox17 plays a central role in the induction of tip cell differentiation. Expression of Sox17 in tip cells induces tip cell behavior, whereas Notch signaling downregulates Sox17 in endothelial cells to induce stalk cell specification. These results contradict with previous observations from Corada et al3 (discussed in insets) who report that Sox17 is a tip cell suppressor, upstream, not downstream, of Notch signaling. Red arrows indicate novel regulatory pathways dissected by Lee et al.2 Ang2 indicates angiopoietin-2; Dll4, Delta-like 4; ESM1, endothelial cell-specific molecule 1; NICD, Notch intracellular domain; and VEGFR2, vascular endothelial growth factor receptor 2. Article, see p 215 Except for a brief period of embryonic vasculogenesis during which the primitive vascular plexus is established, tissues are vascularized …