{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:58:22Z","timestamp":1791503902368,"version":"4.3.4"},"reference-count":151,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>In this review, we discuss the state of our knowledge as it relates to embryonic brain vascular patterning in model systems zebrafish and mouse. We focus on the origins of endothelial cell and the distinguishing features of brain endothelial cells compared to non-brain endothelial cells, which is revealed by single cell RNA-sequencing methodologies. We also discuss the cross talk between brain endothelial cells and neural stem cells, and their effect on each other. In terms of mechanisms, we focus exclusively on Wnt signaling and the recent developments associated with this signaling network in brain vascular patterning, and the benefits and challenges associated with strategies for targeting the brain vasculature. We end the review with a discussion on the emerging areas of meningeal lymphatics, endothelial cilia biology and novel cerebrovascular structures identified in vertebrates.<\/jats:p>","DOI":"10.3389\/fphys.2021.636736","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T17:22:38Z","timestamp":1613236958000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["Established, New and Emerging Concepts in Brain Vascular Development"],"prefix":"10.3389","volume":"12","author":[{"given":"Ankan","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin R.","family":"Rarick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramani","family":"Ramchandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.29738","article-title":"Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI.","volume":"6","author":"Absinta","year":"2017","journal-title":"Elife"},{"key":"B2","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0896-6273(04)00111-4","article-title":"For the long run: maintaining germinal niches in the adult brain.","volume":"41","author":"Alvarez-Buylla","year":"2004","journal-title":"Neuron"},{"key":"B3","doi-asserted-by":"crossref","first-page":"E1936","DOI":"10.1073\/pnas.1421480112","article-title":"SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis.","volume":"112","author":"Amador-Arjona","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.1073\/pnas.1019761108","article-title":"Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor.","volume":"108","author":"Anderson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1093\/cvr\/cvt084","article-title":"Flow detection and calcium signalling in vascular endothelial cells.","volume":"99","author":"Ando","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3645","DOI":"10.1084\/jem.20170391","article-title":"Development and plasticity of meningeal lymphatic vessels.","volume":"214","author":"Antila","year":"2017","journal-title":"J. Exp. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1084\/jem.20142290","article-title":"lymphatic vascular system that drains brain interstitial fluid and macromolecules.","volume":"212","author":"Aspelund","year":"2015","journal-title":"J. Exp. Med."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2017.00101","article-title":"The paravascular pathway for brain waste clearance: current understanding, significance and controversy.","volume":"11","author":"Bacyinski","year":"2017","journal-title":"Front. Neuroanat."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03043","article-title":"Lymph flow induces the postnatal formation of mature and functional meningeal lymphatic vessels.","volume":"10","author":"Balint","year":"2019","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/382638a0","article-title":"Functional interaction of beta-catenin with the transcription factor LEF-1.","volume":"382","author":"Behrens","year":"1996","journal-title":"Nature"},{"key":"B11","article-title":"Endothelial cells may have tissue-specific origins.","volume":"1","author":"Bostrom","year":"2018","journal-title":"J. Cell Biol. Histol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1242\/dev.059881","article-title":"Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling.","volume":"138","author":"Bussmann","year":"2011","journal-title":"Development"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007906","article-title":"TCF\/LEFs and Wnt signaling in the nucleus.","volume":"4","author":"Cadigan","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1038\/26982","article-title":"Drosophila Tcf and Groucho interact to repress Wingless signalling activity.","volume":"395","author":"Cavallo","year":"1998","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nm.4309","article-title":"Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.","volume":"23","author":"Chang","year":"2017","journal-title":"Nat. Med."},{"key":"B16","article-title":"Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage.","volume":"11","author":"Chen","year":"","journal-title":"Nat. Commun."},{"key":"B17","article-title":"Brain endothelial cells are exquisite sensors of age-related circulatory cues.","volume":"441","author":"Chen","year":"","journal-title":"Cell Rep. 30"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/j.celrep.2016.12.044","article-title":"Cilia control vascular mural cell recruitment in vertebrates.","volume":"18","author":"Chen","year":"2017","journal-title":"Cell Rep."},{"key":"B19","article-title":"Reck and Gpr124 are essential receptor cofactors for Wnt7a\/Wnt7b-specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation.","volume":"105","author":"Cho","year":"","journal-title":"Neuron 95"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1016\/j.neuron.2017.08.032","article-title":"Reck and Gpr124 are essential receptor cofactors for Wnt7a\/Wnt7b-specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation.","volume":"95","author":"Cho","year":"","journal-title":"Neuron"},{"key":"B21","doi-asserted-by":"publisher","first-page":"23618","DOI":"10.1073\/pnas.1912409116","article-title":"The in vivo endothelial cell translatome is highly heterogeneous across vascular beds.","volume":"116","author":"Cleuren","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B22","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.cell.2006.10.018","article-title":"Wnt\/beta-catenin signaling in development and disease.","volume":"127","author":"Clevers","year":"2006","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.cell.2012.05.012","article-title":"Wnt\/beta-catenin signaling and disease.","volume":"149","author":"Clevers","year":"2012","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.ydbio.2008.10.020","article-title":"Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122\/Wdr10, partially overlapping with the DNA repair gene Med1\/Mbd4.","volume":"325","author":"Cortellino","year":"2009","journal-title":"Dev. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"5759","DOI":"10.1073\/pnas.1017192108","article-title":"GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier.","volume":"108","author":"Cullen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B26","doi-asserted-by":"publisher","first-page":"291","DOI":"10.2174\/1567202616666191014120156","article-title":"Radial glia-endothelial cells\u2019 bidirectional interactions control vascular maturation and astrocyte differentiation: impact for blood-brain barrier formation.","volume":"16","author":"da Silva","year":"2019","journal-title":"Curr. Neurovasc. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1073\/pnas.0805165106","article-title":"Wnt\/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis.","volume":"106","author":"Daneman","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a020412","article-title":"The blood-brain barrier.","volume":"7","author":"Daneman","year":"2015","journal-title":"Cold Spring Harb. Perspect Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.2967\/jnumed.116.187211","article-title":"Cerebrospinal fluid clearance in alzheimer disease measured with dynamic PET.","volume":"58","author":"de Leon","year":"2017","journal-title":"J. Nucl. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2489","DOI":"10.1242\/dev.009324","article-title":"Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network.","volume":"135","author":"Dessaud","year":"2008","journal-title":"Development"},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.1186\/s12987-017-0068-z","article-title":"Effect of shear stress on iPSC-derived human brain microvascular endothelial cells (dhBMECs).","volume":"14","author":"DeStefano","year":"2017","journal-title":"Fluids Barriers CNS"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2625","DOI":"10.1128\/mcb.15.5.2625","article-title":"Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos.","volume":"15","author":"Du","year":"1995","journal-title":"Mol. Cell Biol."},{"key":"B33","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1016\/j.diff.2011.11.007","article-title":"Primary cilia as biomechanical sensors in regulating endothelial function.","volume":"83","author":"Egorova","year":"2012","journal-title":"Differentiation"},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-25666-4","article-title":"Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.","volume":"8","author":"Eide","year":"2018","journal-title":"Sci. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2806","DOI":"10.1161\/atvbaha.118.311231","article-title":"Characterization of endothelial cilia distribution during cerebral-vascular development in Zebrafish (Danio rerio).","volume":"38","author":"Eisa-Beygi","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s00441-014-1811-2","article-title":"Novel insights into the development and maintenance of the blood-brain barrier.","volume":"355","author":"Engelhardt","year":"2014","journal-title":"Cell Tissue Res."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00324","article-title":"The contribution of CXCL12-expressing radial glia cells to neuro-vascular patterning during human cerebral cortex development.","volume":"8","author":"Errede","year":"2014","journal-title":"Front. Neurosci."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat1178","article-title":"A molecular mechanism for Wnt ligand-specific signaling.","volume":"361","author":"Eubelen","year":"2018","journal-title":"Science"},{"key":"B39","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1182\/blood-2009-12-257832","article-title":"Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction.","volume":"116","author":"Fantin","year":"2010","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1242\/jcs.00973","article-title":"Planar polarity from flies to vertebrates.","volume":"117","author":"Fanto","year":"2004","journal-title":"J. Cell Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1242\/dev.058776","article-title":"Assembly and patterning of the vascular network of the vertebrate hindbrain.","volume":"138","author":"Fujita","year":"2011","journal-title":"Development"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1126\/science.287.5457.1433","article-title":"Mammalian neural stem cells.","volume":"287","author":"Gage","year":"2000","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/cr.2007.53","article-title":"Interactions of primary neuroepithelial progenitor and brain endothelial cells: distinct effect on neural progenitor maintenance and differentiation by soluble factors and direct contact.","volume":"17","author":"Gama Sosa","year":"2007","journal-title":"Cell Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1083\/jcb.200302047","article-title":"VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.","volume":"161","author":"Gerhardt","year":"2003","journal-title":"J. Cell Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.celrep.2014.01.032","article-title":"Endothelial cilia mediate low flow sensing during zebrafish vascular development.","volume":"6","author":"Goetz","year":"2014","journal-title":"Cell Rep."},{"key":"B46","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/nrg2774","article-title":"The primary cilium: a signalling centre during vertebrate development.","volume":"11","author":"Goetz","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"B47","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.ydbio.2008.09.019","article-title":"Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain.","volume":"325","author":"Gorivodsky","year":"2009","journal-title":"Dev. Biol."},{"key":"B48","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nrm1739","article-title":"The cell biology of neurogenesis.","volume":"6","author":"Gotz","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1002\/dvdy.24230","article-title":"Vertebrate nervous system posteriorization: Grading the function of Wnt signaling.","volume":"244","author":"Green","year":"2015","journal-title":"Dev. Dyn."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.577584","article-title":"Cellular origins of the lymphatic endothelium: implications for cancer lymphangiogenesis.","volume":"11","author":"Gutierrez-Miranda","year":"2020","journal-title":"Front. Physiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/s0012-1606(03)00356-7","article-title":"Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling.","volume":"262","author":"Haigh","year":"2003","journal-title":"Dev. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1016\/j.celrep.2015.01.049","article-title":"Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans.","volume":"10","author":"Han","year":"2015","journal-title":"Cell Rep."},{"key":"B53","doi-asserted-by":"crossref","DOI":"10.1038\/sdata.2018.160","article-title":"Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types.","volume":"5","author":"He","year":"2018","journal-title":"Sci. Data"},{"key":"B54","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1002\/dvdy.21472","article-title":"Primary cilia sensitize endothelial cells for fluid shear stress.","volume":"237","author":"Hierck","year":"2008","journal-title":"Dev. Dyn."},{"key":"B55","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.devcel.2010.09.005","article-title":"Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification.","volume":"19","author":"Hikasa","year":"2010","journal-title":"Dev. Cell"},{"key":"B56","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.pediatrneurol.2019.02.018","article-title":"Sickle cell disease and stroke.","volume":"95","author":"Hirtz","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1242\/dev.01039","article-title":"The neural tube patterns vessels developmentally using the VEGF signaling pathway.","volume":"131","author":"Hogan","year":"2004","journal-title":"Development"},{"key":"B58","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.aag2476","article-title":"Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels.","volume":"10","author":"Hupe","year":"2017","journal-title":"Sci. Signal"},{"key":"B59","doi-asserted-by":"publisher","first-page":"16180","DOI":"10.1523\/jneurosci.3020-14.2014","article-title":"Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury.","volume":"34","author":"Iliff","year":"2014","journal-title":"J. Neurosci."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci. Transl Med."},{"key":"B61","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1083\/jcb.200312133","article-title":"Primary cilia of human endothelial cells disassemble under laminar shear stress.","volume":"164","author":"Iomini","year":"2004","journal-title":"J. Cell Biol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/nm0603-685","article-title":"Molecular regulation of vessel maturation.","volume":"9","author":"Jain","year":"2003","journal-title":"Nat. Med."},{"key":"B63","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.51413","article-title":"Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation.","volume":"9","author":"Jambusaria","year":"2020","journal-title":"Elife"},{"key":"B64","doi-asserted-by":"crossref","first-page":"i70","DOI":"10.1093\/cercor\/bhp029","article-title":"A stem cell niche for intermediate progenitor cells of the embryonic cortex.","volume":"1","author":"Javaherian","year":"2009","journal-title":"Cereb. Cortex 19 Suppl."},{"key":"B65","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/jcp.22704","article-title":"Primary cilia regulates the directional migration and barrier integrity of endothelial cells through the modulation of hsp27 dependent actin cytoskeletal organization.","volume":"227","author":"Jones","year":"2012","journal-title":"J. Cell Physiol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1681\/asn.2013121314","article-title":"Endothelial cilia are essential for developmental vascular integrity in zebrafish.","volume":"26","author":"Kallakuri","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"B67","article-title":"Single-cell transcriptome atlas of murine endothelial cells.","volume":"76","author":"Kalucka","year":"2020","journal-title":"Cell 180"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00085","article-title":"Blood vessels as regulators of neural stem cell properties.","volume":"12","author":"Karakatsani","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"B69","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ydbio.2015.07.015","article-title":"Integration of vascular systems between the brain and spinal cord in zebrafish.","volume":"406","author":"Kimura","year":"2015","journal-title":"Dev. Biol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s11357-020-00177-1","article-title":"Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain.","volume":"42","author":"Kiss","year":"2020","journal-title":"Geroscience"},{"key":"B71","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.conb.2016.11.006","article-title":"Metabolism and neurogenesis.","volume":"42","author":"Knobloch","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.ceca.2005.06.022","article-title":"Wnt and calcium signaling: beta-catenin-independent pathways.","volume":"38","author":"Kohn","year":"2005","journal-title":"Cell Calcium."},{"key":"B73","doi-asserted-by":"crossref","DOI":"10.15252\/embr.201847047","article-title":"Cerebrovascular endothelial cells form transient Notch-dependent cystic structures in zebrafish.","volume":"20","author":"Kugler","year":"2019","journal-title":"EMBO Rep."},{"key":"B74","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0168-9525(00)02028-X","article-title":"The Wnt\/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape.","volume":"16","author":"Kuhl","year":"2000","journal-title":"Trends Genet."},{"key":"B75","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1126\/science.1196554","article-title":"Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124.","volume":"330","author":"Kuhnert","year":"2010","journal-title":"Science"},{"key":"B76","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/nrneurol.2016.88","article-title":"Vascular endothelial growth factor: a neurovascular target in neurological diseases.","volume":"12","author":"Lange","year":"","journal-title":"Nat. Rev. Neurol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"924","DOI":"10.15252\/embj.201592372","article-title":"Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis.","volume":"35","author":"Lange","year":"","journal-title":"EMBO J."},{"key":"B78","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1242\/dev.025460","article-title":"Homeodomain-interacting protein kinases (Hipks) promote Wnt\/Wg signaling through stabilization of beta-catenin\/Arm and stimulation of target gene expression.","volume":"136","author":"Lee","year":"2009","journal-title":"Development"},{"key":"B79","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.devcel.2013.05.010","article-title":"In vivo analysis reveals a highly stereotypic morphogenetic pathway of vascular anastomosis.","volume":"25","author":"Lenard","year":"2013","journal-title":"Dev. Cell"},{"key":"B80","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.mod.2015.06.001","article-title":"The vascular niche in adult neurogenesis.","volume":"1","author":"Licht","year":"2015","journal-title":"Mech. Dev. 138 Pt"},{"key":"B81","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1083\/jcb.200806024","article-title":"Wnt\/beta-catenin signaling controls development of the blood-brain barrier.","volume":"183","author":"Liebner","year":"2008","journal-title":"J. Cell Biol."},{"key":"B82","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1146\/annurev.cellbio.20.010403.113126","article-title":"The Wnt signaling pathway in development and disease.","volume":"20","author":"Logan","year":"2004","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/s0896-6273(02)00722-5","article-title":"Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain.","volume":"34","author":"Louissaint","year":"2002","journal-title":"Neuron"},{"key":"B84","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1038\/s41593-018-0227-9","article-title":"CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.","volume":"21","author":"Louveau","year":"2018","journal-title":"Nat. Neurosci."},{"key":"B85","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature14432","article-title":"Structural and functional features of central nervous system lymphatic vessels.","volume":"523","author":"Louveau","year":"2015","journal-title":"Nature"},{"key":"B86","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.expneurol.2007.09.031","article-title":"Multipotent embryonic spinal cord stem cells expanded by endothelial factors and Shh\/RA promote functional recovery after spinal cord injury.","volume":"209","author":"Lowry","year":"2008","journal-title":"Exp. Neurol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1128\/mcb.22.4.1184-1193.2002","article-title":"Negative feedback loop of Wnt signaling through upregulation of conductin\/axin2 in colorectal and liver tumors.","volume":"22","author":"Lustig","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.atherosclerosis.2018.06.818","article-title":"Role of endothelial primary cilia as fluid mechanosensors on vascular health.","volume":"275","author":"Luu","year":"2018","journal-title":"Atherosclerosis"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00626","article-title":"Functions of endothelial cilia in the regulation of vascular barriers.","volume":"8","author":"Ma","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001469","article-title":"Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling.","volume":"11","author":"Ma","year":"2013","journal-title":"PLoS Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.devcel.2009.06.016","article-title":"Wnt\/beta-catenin signaling: components, mechanisms, and diseases.","volume":"17","author":"MacDonald","year":"2009","journal-title":"Dev. Cell"},{"key":"B92","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.tcb.2016.08.002","article-title":"The cilium: cellular antenna and central processing unit.","volume":"27","author":"Malicki","year":"2017","journal-title":"Trends Cell Biol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1089\/lrb.2008.1014","article-title":"Developmental angiogenesis of the central nervous system.","volume":"6","author":"Mancuso","year":"2008","journal-title":"Lymphat. Res. Biol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1161\/atvbaha.119.312749","article-title":"Endothelial beta-catenin signaling supports postnatal brain and retinal angiogenesis by promoting sprouting, tip cell formation, and VEGFR (Vascular Endothelial Growth Factor Receptor) 2 expression.","volume":"39","author":"Martowicz","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/0092-8674(89)90506-0","article-title":"Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis.","volume":"58","author":"McMahon","year":"1989","journal-title":"Cell"},{"key":"B96","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1161\/hypertensionaha.118.11513","article-title":"Preeclampsia and cerebrovascular disease.","volume":"74","author":"Miller","year":"2019","journal-title":"Hypertension"},{"key":"B97","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/s0168-9525(02)02770-1","article-title":"Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation?","volume":"18","author":"Mlodzik","year":"2002","journal-title":"Trends Genet."},{"key":"B98","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.stem.2010.07.007","article-title":"Oxygen in stem cell biology: a critical component of the stem cell niche.","volume":"7","author":"Mohyeldin","year":"2010","journal-title":"Cell Stem Cell"},{"key":"B99","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/s0092-8674(00)80112-9","article-title":"XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.","volume":"86","author":"Molenaar","year":"1996","journal-title":"Cell"},{"key":"B100","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1146\/annurev.neuro.29.051605.112933","article-title":"Noncanonical Wnt signaling and neural polarity.","volume":"29","author":"Montcouquiol","year":"2006","journal-title":"Annu. Rev. Neurosci."},{"key":"B101","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1242\/dev.119.1.97","article-title":"Xwnt-5A: a maternal Wnt that affects morphogenetic movements after overexpression in embryos of Xenopus laevis.","volume":"119","author":"Moon","year":"1993","journal-title":"Development"},{"key":"B102","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s00401-016-1555-z","article-title":"Vascular basement membranes as pathways for the passage of fluid into and out of the brain.","volume":"131","author":"Morris","year":"2016","journal-title":"Acta Neuropathol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1161\/circulationaha.107.710111","article-title":"Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1.","volume":"117","author":"Nauli","year":"2008","journal-title":"Circulation"},{"key":"B104","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1159\/000301135","article-title":"Proliferation but not migration is associated with blood vessels during development of the rostral migratory stream.","volume":"32","author":"Nie","year":"2010","journal-title":"Dev. Neurosci."},{"key":"B105","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/367080a0","article-title":"Dishevelled and armadillo act in the wingless signalling pathway in Drosophila.","volume":"367","author":"Noordermeer","year":"1994","journal-title":"Nature"},{"key":"B106","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1161\/ATVBAHA.118.311893","article-title":"Before the Pump.","volume":"38","author":"Norris","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B107","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/287795a0","article-title":"Mutations affecting segment number and polarity in Drosophila.","volume":"287","author":"Nusslein-Volhard","year":"1980","journal-title":"Nature"},{"key":"B108","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1038\/ncb3045","article-title":"Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells.","volume":"16","author":"Ottone","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"B109","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1161\/circulationaha.119.041433","article-title":"Single-Cell RNA-seq unveils unique transcriptomic signatures of organ-specific endothelial cells.","volume":"142","author":"Paik","year":"2020","journal-title":"Circulation"},{"key":"B110","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1242\/dev.119.1.247","article-title":"Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds.","volume":"119","author":"Parr","year":"1993","journal-title":"Development"},{"key":"B111","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1242\/dev.120.2.369","article-title":"wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo.","volume":"120","author":"Peifer","year":"1994","journal-title":"Development"},{"key":"B112","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.nbd.2016.05.015","article-title":"Suppression of glymphatic fluid transport in a mouse model of Alzheimer\u2019s disease.","volume":"93","author":"Peng","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"B113","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1080\/15476286.2016.1201618","article-title":"Single-cell RNA-sequencing: the future of genome biology is now.","volume":"14","author":"Picelli","year":"2017","journal-title":"RNA Biol."},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0225351","article-title":"Primary cilia are present on endothelial cells of the hyaloid vasculature but are not required for the development of the blood-retinal barrier.","volume":"15","author":"Pollock","year":"2020","journal-title":"PLoS One"},{"key":"B115","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.celrep.2014.12.020","article-title":"GPR124 functions as a WNT7-specific coactivator of canonical beta-catenin signaling.","volume":"10","author":"Posokhova","year":"2015","journal-title":"Cell Rep."},{"key":"B116","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/s41581-018-0021-7","article-title":"Single-cell RNA sequencing for the study of development, physiology and disease.","volume":"14","author":"Potter","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.ydbio.2010.08.036","article-title":"Cranial vasculature in zebrafish forms by angioblast cluster-derived angiogenesis.","volume":"348","author":"Proulx","year":"2010","journal-title":"Dev. Biol."},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2019.00059","article-title":"Patterned vascularization of embryonic mouse forebrain, and neuromeric topology of major human subarachnoidal arterial branches: a prosomeric mapping.","volume":"13","author":"Puelles","year":"2019","journal-title":"Front. Neuroanat."},{"key":"B119","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1160\/th03-09-0582","article-title":"Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor.","volume":"91","author":"Raab","year":"2004","journal-title":"Thromb. Haemost."},{"key":"B120","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/mp.2013.79","article-title":"Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice.","volume":"19","author":"Radjavi","year":"2014","journal-title":"Mol. Psychiatry"},{"key":"B121","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.tcb.2014.11.007","article-title":"Regulation of tissue morphogenesis by endothelial cell-derived signals.","volume":"25","author":"Ramasamy","year":"2015","journal-title":"Trends Cell Biol."},{"key":"B122","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1126\/science.1092053","article-title":"Cell migration: integrating signals from front to back.","volume":"302","author":"Ridley","year":"2003","journal-title":"Science"},{"key":"B123","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/386671a0","article-title":"Mechanisms of angiogenesis.","volume":"386","author":"Risau","year":"1997","journal-title":"Nature"},{"key":"B124","doi-asserted-by":"publisher","first-page":"844","DOI":"10.2174\/1871527311201070844","article-title":"Activin and TGF-beta effects on brain development and neural stem cells.","volume":"11","author":"Rodriguez-Martinez","year":"2012","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"B125","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1242\/dev.129.12.3009","article-title":"Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels.","volume":"129","author":"Roman","year":"2002","journal-title":"Development"},{"key":"B126","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/26989","article-title":"The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors.","volume":"395","author":"Roose","year":"1998","journal-title":"Nature"},{"key":"B127","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1007\/s00018-013-1277-5","article-title":"Neurovascular development and links to disease.","volume":"70","author":"Ruhrberg","year":"2013","journal-title":"Cell Mol. Life Sci."},{"key":"B128","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.36187","article-title":"Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells.","volume":"7","author":"Sabbagh","year":"2018","journal-title":"Elife"},{"key":"B129","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1038\/nrg2042","article-title":"Frizzled\/PCP signalling: a conserved mechanism regulating cell polarity and directed motility.","volume":"8","author":"Seifert","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"B130","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/s0960-9822(99)80310-8","article-title":"Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner.","volume":"9","author":"Sheldahl","year":"1999","journal-title":"Curr. Biol."},{"key":"B131","first-page":"258","article-title":"Effects of cervical-lymphatic blockade on brain edema and infarction volume in cerebral ischemic rats.","volume":"49","author":"Si","year":"2006","journal-title":"Chin. J. Physiol."},{"key":"B132","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1016\/s0092-8674(05)80065-0","article-title":"wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate.","volume":"71","author":"Siegfried","year":"1992","journal-title":"Cell"},{"key":"B133","first-page":"3660","article-title":"Radial glia cells control angiogenesis in the developing cerebral cortex through TGF-beta1 Signaling.","volume":"55","author":"Siqueira","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"B134","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1161\/hypertensionaha.111.189605","article-title":"Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo.","volume":"60","author":"Sorriento","year":"2012","journal-title":"Hypertension"},{"key":"B135","doi-asserted-by":"publisher","first-page":"5102","DOI":"10.1182\/blood-2009-07-230284","article-title":"Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching.","volume":"115","author":"Strasser","year":"2010","journal-title":"Blood"},{"key":"B136","first-page":"F835","article-title":"Drainage of interstitial fluid from different regions of rat brain.","volume":"246","author":"Szentistvanyi","year":"1984","journal-title":"Am. J. Physiol."},{"key":"B137","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.mod.2015.07.001","article-title":"Vascularisation of the central nervous system.","volume":"1","author":"Tata","year":"2015","journal-title":"Mech. Dev. 138 Pt"},{"key":"B138","doi-asserted-by":"publisher","first-page":"13414","DOI":"10.1073\/pnas.1613113113","article-title":"Regulation of embryonic neurogenesis by germinal zone vasculature.","volume":"113","author":"Tata","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.1242\/dev.136507","article-title":"Reck enables cerebrovascular development by promoting canonical Wnt signaling.","volume":"143","author":"Ulrich","year":"2016","journal-title":"Development"},{"key":"B140","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.ydbio.2011.06.037","article-title":"Neurovascular development in the embryonic zebrafish hindbrain.","volume":"357","author":"Ulrich","year":"2011","journal-title":"Dev. Biol."},{"key":"B141","article-title":"WNT7 receptor-ligand interaction enables isoform-specific regulation of Wnt bioavailability.","volume":"33","author":"Vallon","year":"2018","journal-title":"Cell Rep. 25"},{"key":"B142","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.06489","article-title":"Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt\/beta-catenin pathway during brain angiogenesis.","volume":"4","author":"Vanhollebeke","year":"2015","journal-title":"Elife"},{"key":"B143","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nn2074","article-title":"Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain.","volume":"11","author":"Vasudevan","year":"2008","journal-title":"Nat. Neurosci."},{"key":"B144","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1083\/jcb.201706151","article-title":"Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression.","volume":"217","author":"Vion","year":"2018","journal-title":"J. Cell Biol."},{"key":"B145","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.brainres.2014.03.018","article-title":"Bidirectional crosstalk between periventricular endothelial cells and neural progenitor cells promotes the formation of a neurovascular unit.","volume":"1565","author":"Vissapragada","year":"2014","journal-title":"Brain Res."},{"key":"B146","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.cellsig.2007.10.031","article-title":"The first five years of the Wnt targetome.","volume":"20","author":"Vlad","year":"2008","journal-title":"Cell Signal."},{"key":"B147","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1242\/dev.02772","article-title":"Tissue\/planar cell polarity in vertebrates: new insights and new questions.","volume":"134","author":"Wang","year":"2007","journal-title":"Development"},{"key":"B148","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1002\/ana.25928","article-title":"Noninvasive characterization of human glymphatics and meningeal lymphatics in an in vivo model of blood-brain barrier leakage.","volume":"89","author":"Wu","year":"2020","journal-title":"Ann. Neurol."},{"key":"B149","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1016\/j.cell.2015.10.067","article-title":"Establishment and dysfunction of the blood-brain barrier.","volume":"163","author":"Zhao","year":"2015","journal-title":"Cell"},{"key":"B150","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.devcel.2014.08.018","article-title":"Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling.","volume":"31","author":"Zhou","year":"2014","journal-title":"Dev. Cell"},{"key":"B151","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.tins.2005.02.001","article-title":"Neurovascular mechanisms of Alzheimer\u2019s neurodegeneration.","volume":"28","author":"Zlokovic","year":"2005","journal-title":"Trends Neurosci."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.636736\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T02:03:11Z","timestamp":1671242591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.636736\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":151,"alternative-id":["10.3389\/fphys.2021.636736"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.636736","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]},"article-number":"636736"}}