Talk:Neural - Vascular Development

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Cite this page: Hill, M.A. (2019, October 17) Embryology Neural - Vascular Development. Retrieved from


Variations of the Circle of Willis at the End of the Human Embryonic Period

Anat Rec (Hoboken). 2018 Aug;301(8):1312-1319. doi: 10.1002/ar.23794. Epub 2018 Mar 9.

Furuichi K1, Ishikawa A1, Uwabe C2, Makishima H2, Yamada S1,2, Takakuwa T1. Author information 1 Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 2 Congenital Anomaly Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Abstract Variations of the circle of Willis (CW) influence blood supply to the brain and adjacent structures in adults. We examined the formation of the CW in 20 human embryo samples at the end of the embryonic period using 3-D reconstructions of serial histological sections. The CW was closed in all samples, and did not form in a single plane, but was composed of multiple stair-like planes. The artery acutely curved at the caudal part of the CW, namely, at the inlet of the basilar artery and bifurcation of the P1 segment of the posterior cerebral artery (PCA), reflecting flexure of the mesencephalon and diencephalon at this stage. Variations were observed in 17 of 20 samples-only anterior parts (anterior communicating artery [Acom] and anterior cerebral artery [ACA]) in 10 samples, only posterior parts (posterior communicating artery [Pcom]) in one sample, and both anterior and posterior parts in six samples. Variations included the Acom formed as partially duplicated in three samples, duplicated in four, plexiform in three, and no channel as a result of a single azygos ACA in one. The ACA formed as duplicated in two, median ACA in two, and right hypoplasia in one. The Pcom formed in hypoplasia of either side in six samples. Variations observed in this study are similar to those observed in fetuses, neonates, and adults. The P1 segment of PCA was very large in all samples. The present observations indicate that variations in the CW are present from the initiation of CW formation. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.

KEYWORDS: circle of Willis; human embryo; three-dimensional reconstruction; variation PMID: 29457875 DOI: 10.1002/ar.23794

Vascular pattern of the dentate gyrus is regulated by neural progenitors

Brain Struct Funct. 2018 May;223(4):1971-1987. doi: 10.1007/s00429-017-1603-z. Epub 2018 Jan 6.

Pombero A1, Garcia-Lopez R1, Estirado A1, Martinez S2,3.

Neurogenesis is a vital process that begins during early embryonic development and continues until adulthood, though in the latter case, it is restricted to the subventricular zone and the subgranular zone of the dentate gyrus (DG). In particular, the DG's neurogenic properties are structurally and functionally unique, which may be related to its singular vascular pattern. Neurogenesis and angiogenesis share molecular signals and act synergistically, supporting the concept of a neurogenic niche as a functional unit between neural precursors cells and their environment, in which the blood vessels play an important role. Whereas it is well known that vascular development controls neural proliferation in the embryonary and in the adult brain, by releasing neurotrophic factors; the potential influence of neural cells on vascular components during angiogenesis is largely unknown. We have demonstrated that the reduction of neural progenitors leads to a significant impairment of vascular development. Since VEGF is a potential regulator in the neurogenesis-angiogenesis crosstalk, we were interested in assessing the possible role of this molecule in the hippocampal neurovascular development. Our results showed that VEGF is the molecule involved in the regulation of vascular development by neural progenitor cells in the DG. KEYWORDS: Blood vessel development; Dentate gyrus; FGFR1; VEGF. PMID: 29306978 DOI: 10.1007/s00429-017-1603-z


=Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization

Nat Commun. 2017 Jan 10;8:13991. doi: 10.1038/ncomms13991.

Wild R1,2, Klems A1,2, Takamiya M2, Hayashi Y2,3, Strähle U2, Ando K4, Mochizuki N4, van Impel A5,6, Schulte-Merker S5,6, Krueger J7, Preau L1, le Noble F1,2. Author information 1 Department of Cell and Developmental Biology, Institute of Zoology (ZOO) Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 4, 76131 Karlsruhe, Germany. 2 Institute for Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany. 3 Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, 8000 Aarhus C, Denmark. 4 Department of Cell Biology, National Cerebral and Cardiovascular Research Institute, 5-7-1 Fujisirodai, Suita, Osaka 565-8565, Japan. 5 Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, University of Münster, Mendelstr. 7, 48149 Münster, Germany. 6 Cells-in-Motion Cluster of Excellence, (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, 48149 Münster, Germany. 7 Department of Translational Oncology, Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave., M4N 3M5 Toronto, Canada. Abstract Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually, our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode. PMID: 28071661 PMCID: PMC5234075 DOI: 10.1038/ncomms13991

NIH workshop report on the trans-agency blood-brain interface workshop 2016: exploring key challenges and opportunities associated with the blood, brain and their interface

Fluids Barriers CNS. 2017 May 1;14(1):12. doi: 10.1186/s12987-017-0061-6.

Ochocinska MJ1, Zlokovic BV2, Searson PC3, Crowder AT4, Kraig RP5, Ljubimova JY6, Mainprize TG7, Banks WA8, Warren RQ9, Kindzelski A9, Timmer W10, Liu CH10.


A trans-agency workshop on the blood-brain interface (BBI), sponsored by the National Heart, Lung and Blood Institute, the National Cancer Institute and the Combat Casualty Care Research Program at the Department of Defense, was conducted in Bethesda MD on June 7-8, 2016. The workshop was structured into four sessions: (1) blood sciences; (2) exosome therapeutics; (3) next generation in vitro blood-brain barrier (BBB) models; and (4) BBB delivery and targeting. The first day of the workshop focused on the physiology of the blood and neuro-vascular unit, blood or biofluid-based molecular markers, extracellular vesicles associated with brain injury, and how these entities can be employed to better evaluate injury states and/or deliver therapeutics. The second day of the workshop focused on technical advances in in vitro models, BBB manipulations and nanoparticle-based drug carrier designs, with the goal of improving drug delivery to the central nervous system. The presentations and discussions underscored the role of the BBI in brain injury, as well as the role of the BBB as both a limiting factor and a potential conduit for drug delivery to the brain. At the conclusion of the meeting, the participants discussed challenges and opportunities confronting BBI translational researchers. In particular, the participants recommended using BBI translational research to stimulate advances in diagnostics, as well as targeted delivery approaches for detection and therapy of both brain injury and disease. KEYWORDS: Blood–brain barrier; Cancer; Delivery; Exosomes; Extracellular vesicles; Neurodegeneration; Therapeutics; Traumatic brain injury

PMID 28457227 PMCID: PMC5410699 DOI: 10.1186/s12987-017-0061-6


Formation of the circle of Willis during human embryonic development

Congenit Anom (Kyoto). 2016 Mar 31. doi: 10.1111/cga.12165. [Epub ahead of print]

Takakuwa T1, Koike T1, Muranaka T1, Uwabe C2, Yamada S1,2.


The circle of Willis (CW) is a circulatory anastomosis that supplies blood to the brain and adjacent structures. We examined the timing of formation of CW in 20 Japanese human embryo samples by using 3-dimensional reconstruction of serial histological sections. The CW was closed in 1 (n = 6), 2 (n = 8), 2 (n = 3) and 2 (n = 3) samples at Carnegie stages 20, 21, 22, and 23, respectively. The CW was unclosed in 13 samples (unclosed at ACOM alone, 6 samples; ACOM and bilateral P1, 4; left PCOM and right P1, 1; right PCOM and right P1, 1; ACOM and left PCOM, 1). It was difficult to predict whether the circle would close during further development, as such variations frequently exist in adults. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. KEYWORDS: Circle of Willis; human embryo; three-dimensional reconstruction

PMID 27037515


Differentiation of blood-brain barrier endothelial cells

Pathol Biol (Paris). 1998 Mar;46(3):171-5.

Risau W1, Esser S, Engelhardt B.


The vascular system of the central nervous system is derived from capillary endothelial cells, which have invaded the early embryonic neuroectoderm from the perineural vascular plexus. This process is called angiogenesis and is probably regulated by brain-derived factors. Vascular endothelial cell growth factor (VEGF) is an angiogenic growth factor whose expression correlated with embryonic brain angiogenesis, i.e. expression is high in the embryonic brain when angiogenesis occurs and low in the adult brain when angiogenesis is shut off under normal physiological conditions. VEGF receptors 1 and 2 (flt-1 and flk-1) as well as the recently identified angiopoietin receptors (tie-1 and tie-2) are receptor tyrosine kinases specifically expressed in endothelial cells. Expression of these receptors is high during brain angiogenesis but low in adult blood-brain barrier endothelium. They are required for the proper development of a vascular system, and particularly tie-2 is necessary for brain angiogenesis. Signal transduction by these receptors regulates endothelial cell growth, permeability and differentiation. Blood-brain barrier endothelial cell characteristics (complex tight junctions, low number of vesicles, specialized transport systems) are induced by the local brain environment, e.g. neurons and astrocytes. Tight junctions between brain endothelial cells are the structural basis for the paracellular impermeability and high electrical resistance of blood-brain barrier endothelium. Association of tight junction particles with the P-face rather than the number or branching frequency of tight junction stands correlated with blood-brain barrier development and function suggesting that the cytoplasmic anchoring of the tight junctions plays an important role. During inflammation, leukocytes migrate through blood-brain barrier endothelium. ICAM-1 and VCAM-1 on blood-brain barrier endothelial cells appear to be the major mediators of these processes while the selectins are absent from brain endothelium in vivo.

PMID 9769912


Fine structural localization of a blood-brain barrier to exogenous peroxidase

J Cell Biol. 1967 Jul;34(1):207-17.

Reese TS, Karnovsky MJ.


Horseradish peroxidase was administered to mice by intravenous injection, and its distribution in cerebral cortex studied with a recently available technique for localizing peroxidase with the electron microscope. Brains were fixed by either immersion or vascular perfusion 10-60 min after administration of various doses of peroxidase. Exogenous peroxidase was localized in the lumina of blood vessels and in some micropinocytotic vesicles within endothelial cells; none was found beyond the vascular endothelium. Micropinocytotic vesicles were few in number and did not appear to transport peroxidase while tight junctions between endothelial cells were probably responsible for preventing its intercellular passage. Our findings therefore localize, at a fine structural level, a "barrier" to the passage of peroxidase at the endothelium of vessels in the cerebral cortex. The significance of these findings is discussed, particularly with reference to a recent study in which similar techniques were applied to capillaries in heart and skeletal muscle.

PMID 6033532 PMCID: PMC2107213