Cardiovascular System - Blood Vessel Development

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Introduction

Developing Blood Vessel

Blood develops initially within the core of "blood islands" in the mesoderm. During development, there follows a series of "relocations" of the stem cells to different organs within the embryo. In the adult, these stem cells are located in the bone marrow. At the time when blood first forms, there are no bones!

Vasculogenesis Angiogenesis
formation of new blood vessels
(endothelium from mesoderm)
formation of blood vessels from pre-existing vessels
(occurs in development and adult)

Angioblasts initially form small cell clusters (blood islands) within the embryonic and extraembryonic mesoderm. These blood islands extend and fuse together making a primordial vascular network. Within these islands the peripheral cells form endothelial cells while the core cells form blood cells (haemocytoblasts).

Recent work has shown that the formation of the initial endothelial tube is by a process of coalescence of cellular vacuoles within the developing endothelial cells, which fuse together without cytoplasmic mixing to form the blood vessel lumen.

See also the related pages Placental Villi Blood Vessels and Coronary Circulation Development.

Cardiovascular Links: Introduction | Heart Tutorial | Lecture - Early Vascular | Lecture - Heart | Movies | Heart | Coronary Circulation | Heart Valve | Heart Rate | Circulation | Blood | Blood Vessel | Blood Vessel Histology | Cardiac Muscle Histology | Lymphatic | Ductus Venosus | Spleen | Stage 22 | Abnormalities | OMIM | ECHO Meeting | Category:Cardiovascular
Historic Embryology
1912 Heart | 1912 Human Heart | 1915 Congenital Cardiac Disease | 1916 Pars Membranacea Septi | 1921 Human Brain Vascular | 1923 Head Subcutaneous Plexus | 1922 Aortic-Arch System | 1922 Pig Forelimb Arteries | 1922 Chicken Pulmonary | 1938 Pars Membranacea Septi | Ziegler Heart Models | Historic Disclaimer


Developmental Signals - Vascular Endothelial Growth Factor | Smooth Muscle Development

Some Recent Findings

Adult human cardiovascular system
  • Review - The Molecular Regulation of Arteriovenous Specification and Maintenance[1] "The formation of a hierarchical vascular network, composed of arteries, veins and capillaries, is essential for embryogenesis and is required for the production of new functional vasculature in the adult. Elucidating the molecular mechanisms that orchestrate the differentiation of vascular endothelial cells into arterial and venous cell fates is requisite for regenerative medicine, as the directed formation of perfused vessels is desirable in a myriad of pathological settings, such as in diabetes and following myocardial infarction. Additionally, this knowledge will enhance our understanding and treatment of vascular anomalies, such as arteriovenous malformations (AVMs). From studies in vertebrate model organisms, such as mouse, zebrafish and chick, a number of key signaling pathways have been elucidated that are required for the establishment and maintenance of arterial and venous fates. These include the Hedgehog, Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor-β (TGF-β), Wnt and Notch signaling pathways. In addition, a variety of transcription factor families acting downstream of-or in concert with-these signaling networks play vital roles in arteriovenous (AV) specification. These include Notch and Notch-regulated transcription factors (e.g. HEY and HES), SOX factors, Forkhead factors, β-Catenin, ETS factors and COUP-TFII. It is becoming apparent that AV specification is a highly coordinated process that involves the intersection and carefully orchestrated activity of multiple signaling cascades and transcriptional networks. This review will summarize the molecular mechanisms that are involved in the acquisition and maintenance of AV fate, and will highlight some of the limitations in our current knowledge of the molecular machinery that directs AV morphogenesis.
  • Specification of arterial, venous, and lymphatic endothelial cells during embryonic development [2] "The groundbreaking discovery about arterial and venous expression of ephrinB2 and EphB4, respectively, in early embryonic development has led to a new paradigm for vascular research, providing compelling evidence that arterial and venous endothelial cells are established by genetic mechanisms before circulation begins. For arterial specification, vascular endothelial growth factor (VEGF) induces expression of Notch signaling genes, including Notch1 and its ligand, Delta-like 4 (Dll4), and Foxc1 and Foxc2 transcription factors directly regulate Dll4 expression. Upon activation of Notch signaling, the Notch downstream genes, Hey1/2 in mice or gridlock in zebrafish, further promote arterial differentiation. On the other hand, the orphan nuclear receptor COUP-TFII is a determinant factor for venous specification by inhibiting expression of arterial specific genes, including Nrp1 and Notch. After arterial and venous endothelial cells differentiate, a subpopulation of venous endothelial cells is thought to become competent to acquire lymphatic endothelial cell fate by progressively expressing the transcription factors Sox18 and Prox1 to differentiate into lymphatic endothelial cells."
  • Developmental origin of smooth muscle cells in the descending aorta in mice[3] "Aortic smooth muscle cells (SMCs) have been proposed to derive from lateral plate mesoderm. ....(these results) suggested that all SMCs in the adult descending aorta derive from the somites, whereas no contribution was recorded from lateral plate mesoderm."
  • Notch ligand Jagged1 is required for vascular smooth muscle development[4] "The Notch ligand Jagged1 (Jag1) is essential for vascular remodeling. ...Jag1 null phenotype. These embryos show striking deficits in vascular smooth muscle, whereas endothelial Notch activation and arterial-venous differentiation appear normal."
More recent papers
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  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
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Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Blood Vessel Embryology

Dragoş Cătălin Jianu, Silviana Nina Jianu, Ligia Petrica, Andrei Gheorghe Marius Motoc, Traian Flavius Dan, Dorela CodruŢa Lăzureanu, Mihnea Munteanu Clinical and color Doppler imaging features of one patient with occult giant cell arteritis presenting arteritic anterior ischemic optic neuropathy. Rom J Morphol Embryol: 2016, 57(2);579-83 PubMed 27516038

Izabela Mróz, Stanislas Kielczewski, Dominik Pawlicki, Wojciech Kurzydło, Piotr Bachul, Monika Konarska, Tomasz Bereza, Klaudia Walocha, Lourdes Niroja Kaythampillai, Paweł Depukat, Artur Pasternak, Tomasz Bonczar, Przemysław Chmielewski, Ewa Mizia, Janusz Skrzat, Małgorzata Mazur, Łukasz Warchoł, Krzysztof Tomaszewski Blood vessels of the shin - anterior tibial artery - anatomy and embryology - own studies and review of the literature. Folia Med Cracov: 2016, 56(1);33-47 PubMed 27513837

Gregor Weiss, Monika Sundl, Andreas Glasner, Berthold Huppertz, Gerit Moser The trophoblast plug during early pregnancy: a deeper insight. Histochem. Cell Biol.: 2016; PubMed 27510415

Yahya Guvenc, Adnan Demirci, Deniz Billur, Sevim Aydin, Ersin Ozeren, Pinar Bayram, Alper Dilli, Emre Cemal Gokce, Onur Yaman, Haydar Celik, Mete Karatay, Fatih Alagoz, Erkan Kaptanoglu Punica granatum L. Juice Attenuates Experimental Cerebral Vasospasm in the Rabbit Subarachnoid Hemorrhage Model: A Basilar Artery Morphometric Study and Apoptosis. J Neurol Surg A Cent Eur Neurosurg: 2016; PubMed 27509316

Arda Cetinkaya, Jingwei Rachel Xiong, İbrahim Vargel, Kemal Kösemehmetoğlu, Halil İbrahim Canter, Ömer Faruk Gerdan, Nicola Longo, Ahmad Alzahrani, Mireia Perez Camps, Ekim Zihni Taskiran, Simone Laupheimer, Lorenzo D Botto, Eeswari Paramalingam, Zeliha Gormez, Elif Uz, Bayram Yuksel, Şevket Ruacan, Mahmut Şamil Sağıroğlu, Tokiharu Takahashi, Bruno Reversade, Nurten Ayse Akarsu Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling. Am. J. Hum. Genet.: 2016; PubMed 27476657

Endothelial Progenitors

Recent work has shown that the formation of the initial endothelial tube is by a process of coalescence of cellular vacuoles within the developing endothelial cells, which fuse together without cytoplasmic mixing to form the blood vessel lumen. [5]

Endothelial Tube Formation

Blood vessel lumen formation cartoon

Blood vessel lumen formation

Vessel Specification

Embryonic Circulations

The following data is from a recent review.[2]

Arterial Specification

Factor Function
Shh Loss of Shh results in lack of arterial identity in zebrafish. Shh acts upstream of VEGF.
VEGF VEGF acts downstream of Shh signaling to activate Notch via the PLCγ/ERK pathway in zebrafish. Mutant mice expressing only VEGF188 lack arterial differentiation.
Nrp1 Null mice display impaired arterial differentiation. Nrp1 is involved in a positive feedback loop of VEGF signaling.
Notch Notch acts downstream of Shh and VEGF signaling in zebrafish. Notch1; Notch4 mutant mice have abnormal vascular development.
Dll4 Null mice lack arterial specification.
Dll1 Null mice fail to maintain arterial identity.
Hey1/2 (Grl) Null mice lack arterial specification. Lack of grl in zebrafish results in loss of arterial specification.
Foxc1/c2 Foxc1; Foxc2 mutant mice lack arterial specification. Foxc1 and Foxc2 directly regulate Dll4 and Hey2 expression. Foxc1 and Foxc2 are also involved in lymphatic vessel development.
Sox7/18 Lack of Sox7/18 results in loss of arterial identity in zebrafish.
Snrk-1 Snrk-1 acts downstream or parallel to Notch signaling in zebrafish.
Dep1 Dep1 acts upstream of PI3K in arterial specification in zebrafish.
Crlr Shh regulates VEGF activity by controlling crlr expression in zebrafish.
EphrinB2 Null mice lack boundaries between arteries and veins. EphrinB2 is involved in lymphatic vascular remodeling and maturation.

Venous Specification

Factor Function
COUP-TFII COUP-TFII suppresses arterial cell fate by inhibiting Nrp1 and Notch. COUP-TFII also interacts with Prox1 to regulate lymphatic gene expression.
EphB4 Null mice lack boundaries between arteries and veins.

Lymphatic Specification

Factor Function
Sox18 Null mice fail to specify lymphatic endothelial cells. Sox18 induces Prox1 expression.
Prox1 Prox1 induces lymphatic markers and maintains lymphatic cell identity.

Vascular Endothelial Growth Factor

Growing blood vessels follow a gradient generated by tagret tissues/regions of Vascular Endothelial Growth Factor (VEGF) to establish a vascular bed. Recent findings suggest that Notch signaling acts as an inhibitor for this system, preventing sprouting of blood vessels.

Notch is a transmembrane receptor protein involved in regulating cell differentiation in many developing systems.

Notch and yolk sac blood vessels model.jpg Vascular formation cartoon1.jpg
Notch and yolk sac blood vessels model[6] Vasculogenesis and angiogenesis[7]


Links: OMIM - VEGFA | OMIM - Notch

Regulators of Growth

The following data is from a review article on ovary vascular development.[8]

Stimulators of Angiogenisis

  • Peptide growth factors
    • Vascular endothelial growth factor-Aa,b, -Bb, -Cb, -D
    • [-E], -F (VEGF-Aa,b, -Bb, -Cb, -Db, -E, -F)
    • Placenta growth factor (PlGF)
    • Angiopoietin-1 (Ang-1)
    • Angiopoietin-2 (Ang-2) [modulator in the presence of angiogenic activity]
    • Acidic fibroblast growth factor (FGF-1)
    • Basic fibroblast growth factor (FGF-2)
    • Platelet-derived growth factor (PDGF)
    • Transforming growth factor-a (TGF-a)
    • Transforming growth factor-b (TGF-b)
    • Hepatocyte growth factor (HGF)
    • Insulin-like growth factor-I (IGF-I)
  • Multifunctional cytokines/immune mediators
    • Tumour necrosis factor-a (low-dose)
    • Monocyte chemoattractant protein-1 (MCP-1)
  • CXC-chemokines
    • Interleukin-8 (IL-8)
  • Enzymes
    • Platelet-derived endothelial cell growth factor
    • (PD-ECGF; thymidine phosphorylase)
  • Angiogenin (ribonuclease A homologue)
  • Hormones
    • Oestrogens
    • Prostaglandin-E1, -E2
    • Follistatin
    • Proliferin
  • Oligosaccharides
    • Hyaluronan oligosaccharides
    • Gangliosides

Inhibitors of Angiogenisis

  • Peptide growth factors and proteolytic peptides
    • Angiopoietin-2 (Ang-2) [in the absence of angiogenic activity]
    • Angiostatin
    • Endostatin
    • 16 kDa prolactin fragment
    • Laminin peptides
    • Fibronectin peptides
  • Inhibitors of enzymatic activity
    • Tissue metalloproteinase inhibitors
    • (TIMP-1, -2, -3, -4)
    • Plasminogen activator inhibitors
    • (PAI-1, -2)
  • Multifunctional cytokines/immune mediators
    • Tumour necrosis factor-a (high-dose)
    • Interferons
    • Interleukin-12
  • CXC-chemokines
    • Platelet factor-4 (PF-4)
    • Interferon-gamma-inducible protein-10 (IP-10)
    • Gro-beta
  • Extracellular matrix molecules
    • Thrombospondin
  • Hormones/metabolites
    • 2-Methoxyestradiol (2-ME)
    • Proliferin-related protein
  • Oligosaccharides
    • Hyaluronan, high-molecular-weight species

Histology

Vein Light Microscopy

Vein histology 01.jpg

The entire developing and adult cardiovascular system (blood vessels and heart) is lined by a simple squamous epithelium. (Stain - Haematoxylin Eosin)


Capillaries

Electron Micrographs

Blood capillary EM 04.jpg

Arteries

Cardiac Blood Vessels

Earliest vessels in the heart wall develop subepicardially (beneath the outside surface of the heart) near the apex at Carnegie stage 15, which then extends centripetally and at stage 17 coronary arterial stems communicate with the aortic lumen.[10]

Abnormalities

Due to the extensive embryonic, and ongoing, remodelling of the vascular system, there are many different vascular variations and anomalies.

Neural

Trigeminal artery 01.jpg

Persistent trigeminal and hypoglossal arteries[11]


Links: Cerebrum Development | Head Development

References

  1. Jason E Fish, Joshua D Wythe The Molecular Regulation of Arteriovenous Specification and Maintenance. Dev. Dyn.: 2015; PubMed 25641373
  2. 2.0 2.1 Tsutomu Kume Specification of arterial, venous, and lymphatic endothelial cells during embryonic development. Histol. Histopathol.: 2010, 25(5);637-46 PubMed 20238301 | PMC2899674
  3. Per Wasteson, Bengt R Johansson, Tomi Jukkola, Silke Breuer, Levent M Akyürek, Juha Partanen, Per Lindahl Developmental origin of smooth muscle cells in the descending aorta in mice. Development: 2008, 135(10);1823-32 PubMed 18417617
  4. Frances A High, Min Min Lu, Warren S Pear, Kathleen M Loomes, Klaus H Kaestner, Jonathan A Epstein Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc. Natl. Acad. Sci. U.S.A.: 2008, 105(6);1955-9 PubMed 18245384
  5. Morayma Reyes, Arkadiusz Dudek, Balkrishna Jahagirdar, Lisa Koodie, Paul H Marker, Catherine M Verfaillie Origin of endothelial progenitors in human postnatal bone marrow. J. Clin. Invest.: 2002, 109(3);337-46 PubMed 11827993
  6. Jessica N Copeland, Yi Feng, Naveen K Neradugomma, Patrick E Fields, Jay L Vivian Notch signaling regulates remodeling and vessel diameter in the extraembryonic yolk sac. BMC Dev. Biol.: 2011, 11;12 PubMed 21352545 | BMC Dev Biol.
  7. Yoh Takuwa, Wa Du, Xun Qi, Yasuo Okamoto, Noriko Takuwa, Kazuaki Yoshioka Roles of sphingosine-1-phosphate signaling in angiogenesis. World J Biol Chem: 2010, 1(10);298-306 PubMed 21537463
  8. H G Augustin Vascular morphogenesis in the ovary. Baillieres Best Pract Res Clin Obstet Gynaecol: 2000, 14(6);867-82 PubMed 11141338
  9. Benoit Detry, Françoise Bruyère, Charlotte Erpicum, Jenny Paupert, Françoise Lamaye, Catherine Maillard, Bénédicte Lenoir, Jean-Michel Foidart, Marc Thiry, Agnès Noël Digging deeper into lymphatic vessel formation in vitro and in vivo. BMC Cell Biol.: 2011, 12;29 PubMed 21702933 | PMC3141733 | BMC Cell Biol.
  10. K Turner, V Navaratnam The positions of coronary arterial ostia. Clin Anat: 1996, 9(6);376-80 PubMed 8915616
  11. Khaled Menshawi, Jay P Mohr, Jose Gutierrez A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood Supply. J Stroke: 2015, 17(2);144-58 PubMed 26060802 | J Stroke.

Reviews

Jason E Fish, Joshua D Wythe The Molecular Regulation of Arteriovenous Specification and Maintenance. Dev. Dyn.: 2015; PubMed 25641373


Articles

A J Davidson, L I Zon Turning mesoderm into blood: the formation of hematopoietic stem cells during embryogenesis. Curr. Top. Dev. Biol.: 2000, 50;45-60 PubMed 10948449

Kathleen E McGrath, Anne D Koniski, Jeffrey Malik, James Palis Circulation is established in a stepwise pattern in the mammalian embryo. Blood: 2003, 101(5);1669-76 PubMed 12406884


Search Pubmed

Click on the listed keywords below (used to search the external database) the most current references on Medline will be displayed.

Search Pubmed: Blood Vessel Development | Blood Vessel embryology | Blood Vessel smooth muscle Development | Blood Vessel smooth muscle Development

Terms

Cardiovascular Terms  
Cardiovascular System Development See also Heart terms
  • angioblast - the stem cells in blood islands generating endothelial cells which will form the walls of both arteries and veins. (More? Blood Vessel)
  • angiogenesis - the formation of new blood vessels from pre-existing vessels following from vasculogenesis in the embryo. (More? Blood Vessel)
  • anlage (German, anlage = primordium) structure or cells which will form a future more developed or differentiated adult structure.
  • blood islands - earliest sites of blood vessel and blood cell formation, seen mainly on yolk sac chorion.
  • cardinal veins - paired main systemic veins of early embryo, anterior, common, posterior.
  • cardiogenic region - region above prechordal plate in mesoderm where heart tube initially forms.
  • ectoderm - the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.
  • endoderm - the layer (of the 3 germ cell layers) which form the epithelial lining of the gastrointestinal tract (GIT) and accessory organs of GIT in the embryo.
  • endocardium - lines the heart. Epithelial tissue lining the inner surface of heart chambers and valves.
  • endothelial cells - single layer of cells closest to lumen that line blood vessels.
  • extraembryonic mesoderm - mesoderm lying outside the trilaminar embryonic disc covering the yolk sac, lining the chorionic sac and forming the connecting stalk. Contributes to placental villi development.
  • haemocytoblasts - stem cells for embryonic blood cell formation.
  • anastomose - to connect or join by a connection (anastomosis) between tubular structures.
  • chorionic villi - the finger-like extensions which are the functional region of the placental barrier and maternal/fetal exchange. Develop from week 2 onward as: primary, secondary, tertiary villi.
  • estrogens - support the maternal endometrium.
  • growth factor - usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg VEGF, shh)
  • maternal decidua - region of uterine endometrium where blastocyst implants. undergoes modification following implantation, decidual reaction.
  • maternal sinusoids - placental spaces around chorionic villi that are filled with maternal blood. Closest maternal/fetal exchange site.
  • mesoderm - the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.
  • myocardium - muscular wall of the heart. Thickest layer formed by spirally arranged cardiac muscle cells.
  • pericardium - covers the heart. Formed by 3 layers consisting of a fibrous pericardium and a double layered serous pericardium (parietal layer and visceral epicardium layer).
  • pharyngeal arches (=branchial arches, Gk. gill) series of cranial folds that form most structures of the head and neck. Six arches form but only 4 form any structures. Each arch has a pouch, membrane and groove.
  • placenta - (Greek, plakuos = flat cake) refers to the discoid shape of the placenta, embryonic (villous chorion)/maternal organ (decidua basalis)
  • placental veins - paired initially then only left at end of embryonic period, carry oxygenated blood to the embryo (sinus venosus).
  • protein hormone - usually a protein distributed in the blood that binds to membrane receptors on target cells in different tissues. Do not easliy cross placental barrier.
  • sinus venosus - cavity into which all major embryonic paired veins supply (vitelline, placental, cardinal).
* splanchnic mesoderm - portion of lateral plate mesoderm closest to the endoderm when coelom forms. 
  • steroid hormone - lipid soluble hormone that easily crosses membranes to bind receptors in cytoplasm or nucleus of target cells. Hormone+Receptor then binds DNA activating or suppressing gene transcription. Easliy cross placental barrier.
  • syncitiotrophoblast extraembryonic cells of trophoblastic shell surrounding embryo, outside the cytotrophoblast layer, involved with implantation of the blastocyst by eroding extracellular matrix surrounding maternal endometrial cells at site of implantation, also contribute to villi. (dark staining, multinucleated).
  • truncus arteriosus - an embryological heart outflow structure, that forms in early cardiac development and will later divides into the pulmonary artery and aorta. Term is also used clinically to describe the malformation where only one artery arises from the heart and forms the aorta and pulmonary artery.
  • vascular endothelial growth factor - (VEGF) A secreted protein growth factor family, which stimulates the proliferation of vasular endotheial cells and therefore blood vessel growth. VEGF's have several roles in embryonic development. The VEGF family has 7 members (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PlGF) that have a common VEGF homology domain. PIGF is the placental growth factor. They act through 3 VEGF tyrosine kinase membrane receptors (VEGFR-1 to 3) with seven immunoglobulin-like domains in the extracellular domain, a single transmembrane region, and an intracellular tyrosine kinase sequence.
  • vasculogenesis - the formation of new blood vessels from mesoderm forming the endothelium. Compared to angiogenesis that is the process of blood vessel formation from pre-existing vessels.
  • vitelline blood vessels - blood vessels associated with the yolk sac.
  • waste products - products of cellular metabolism and cellular debris, e.g.- urea, uric acid, bilirubin.
Other Terms Lists  
Terms Lists: ART | Birth | Bone | Cardiovascular | Gastrointestinal | Genetic | Hearing | Heart | Immune | Integumentary | Neural | Oocyte | Palate | Placenta | Renal | Spermatozoa | Ultrasound | Vision | Historic | Glossary

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Cite this page: Hill, M.A. (2016) Embryology Cardiovascular System - Blood Vessel Development. Retrieved August 29, 2016, from https://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Blood_Vessel_Development

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© Dr Mark Hill 2016, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G