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!
Note that blood vessel development is tightly coupled to development of other systems for example: osteogenesis (bone formation) that is dependent upon early capillary formation; endocrine development that requires blood vessels for hormone distribution.
|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 Arterial Development, Venous Development, Placental Villi Blood Vessels and Coronary Circulation Development.
- Developmental Signals - Vascular Endothelial Growth Factor | Smooth Muscle Development
Some Recent Findings
Adult human cardiovascular system
- Cell-matrix signals specify bone endothelial cells during developmental osteogenesis “Blood vessels in the mammalian skeletal system control bone formation and support haematopoiesis by generating local niche environments. Here, we report that embryonic and early postnatal long bone contains a specialized endothelial cell subtype, termed type E, which strongly supports osteoblast lineage cells and later gives rise to other endothelial cell subpopulations. The differentiation and functional properties of bone endothelial cells require cell-matrix signalling interactions." Bone Development | INTEGRIN BETA-1
- Endothelium in the pharyngeal arches 3, 4 and 6 is derived from the second heart field "Oxygenated blood from the heart is directed into the systemic circulation through the aortic arch arteries (AAAs). The AAAs arise by remodeling of three symmetrical pairs of pharyngeal arch arteries (PAAs), which connect the heart with the paired dorsal aortae at mid-gestation. Aberrant PAA formation results in defects frequently observed in patients with lethal congenital heart disease. How the PAAs form in mammals is not understood. The work presented in this manuscript shows that the second heart field (SHF) is the major source of progenitors giving rise to the endothelium of the pharyngeal arches 3 - 6, while the endothelium in the pharyngeal arches 1 and 2 is derived from a different source. During the formation of the PAAs 3 - 6, endothelial progenitors in the SHF extend cellular processes toward the pharyngeal endoderm, migrate from the SHF and assemble into a uniform vascular plexus. This plexus then undergoes remodeling, whereby plexus endothelial cells coalesce into a large PAA in each pharyngeal arch."
- Review - The Molecular Regulation of Arteriovenous Specification and Maintenance "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."
|More recent papers
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Search term: Blood Vessel Embryology
<pubmed limit=5>Blood Vessel Embryology</pubmed>
- Specification of arterial, venous, and lymphatic endothelial cells during embryonic development  "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 "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 "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."
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. 
Endothelial Tube Formation
Blood vessel lumen formation
The following data is from a recent review.
||Loss of Shh results in lack of arterial identity in zebrafish. Shh acts upstream of 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.
||Null mice display impaired arterial differentiation. Nrp1 is involved in a positive feedback loop of VEGF signaling.
||Notch acts downstream of Shh and VEGF signaling in zebrafish. Notch1; Notch4 mutant mice have abnormal vascular development.
||Null mice lack arterial specification.
||Null mice fail to maintain arterial identity.
||Null mice lack arterial specification. Lack of grl in zebrafish results in loss of arterial specification.
||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.
||Lack of Sox7/18 results in loss of arterial identity in zebrafish.
||Snrk-1 acts downstream or parallel to Notch signaling in zebrafish.
||Dep1 acts upstream of PI3K in arterial specification in zebrafish.
||Shh regulates VEGF activity by controlling crlr expression in zebrafish.
||Null mice lack boundaries between arteries and veins. EphrinB2 is involved in lymphatic vascular remodeling and maturation.
||COUP-TFII suppresses arterial cell fate by inhibiting Nrp1 and Notch. COUP-TFII also interacts with Prox1 to regulate lymphatic gene expression.
||Null mice lack boundaries between arteries and veins.
||Null mice fail to specify lymphatic endothelial cells. Sox18 induces Prox1 expression.
||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
||Vasculogenesis and angiogenesis
Links: OMIM - VEGFA | OMIM - Notch
Regulators of Growth
The following data is from a review article on ovary vascular development.
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)
- Platelet-derived endothelial cell growth factor
- (PD-ECGF; thymidine phosphorylase)
- Angiogenin (ribonuclease A homologue)
- Prostaglandin-E1, -E2
- Hyaluronan oligosaccharides
Inhibitors of Angiogenisis
- Peptide growth factors and proteolytic peptides
- Angiopoietin-2 (Ang-2) [in the absence of angiogenic activity]
- 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)
- Platelet factor-4 (PF-4)
- Interferon-gamma-inducible protein-10 (IP-10)
- Extracellular matrix molecules
- 2-Methoxyestradiol (2-ME)
- Proliferin-related protein
- Hyaluronan, high-molecular-weight species
Vein Light Microscopy
The entire developing and adult cardiovascular system (blood vessels and heart) is lined by a simple squamous epithelium. (Stain - Haematoxylin Eosin)
A developmental capillary endothelial cell subtype associated with osteogenesis, located at the metaphysis and endosteum of postnatal long bone, that couples angiogenesis with osteogenesis. This endothelial cell subtype expresses the markers CD31/PECAM1 and endomucin (CD31hi Emcnhi).
A newly identified endothelial cell subtype similar to type H in function, supporting osteoblast lineage cells and then gives rise to other endothelial cell subpopulations, but this subtype is found in embryonic and early postnatal long bone.
Capillary 1 large labeled
Capillary 1 large unlabelled
Capillary 1 small labeled
Capillary 1 small unlabelled
Containing white blood cell
Artery tunica media elastin
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.
Due to the extensive embryonic, and ongoing, remodelling of the vascular system, there are many different vascular variations and anomalies.
Persistent trigeminal and hypoglossal arteries
- Links: Cerebrum Development | Head Development
- ↑ 1.0 1.1 <pubmed>28218908</pubmed>
- ↑ <pubmed>27955943</pubmed>
- ↑ <pubmed>25641373</pubmed>
- ↑ 4.0 4.1 <pubmed>20238301</pubmed>| PMC2899674
- ↑ <pubmed>18417617</pubmed>
- ↑ <pubmed>18245384</pubmed>
- ↑ <pubmed>11827993</pubmed>
- ↑ <pubmed>21352545</pubmed>| BMC Dev Biol.
- ↑ <pubmed>21537463</pubmed>
- ↑ <pubmed>11141338</pubmed>
- ↑ <pubmed>21702933</pubmed>| PMC3141733 | BMC Cell Biol.
- ↑ <pubmed>8915616</pubmed>
- ↑ <pubmed>26060802</pubmed>| J Stroke.
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
|Cardiovascular System Development See also Heart terms, Immune terms and Blood 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)
- intra-aortic hematopoietic cluster - (IAHC) blood stem cells associated with the endothelial layer of aorta and large arteries.
- 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.
- Megakaryocytopoiesis - the process of bone marrow progenitor cells developMENT into mature megakaryocytes.
- 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).
- pericytes - (Rouget cells) cells located at the abluminal surface of microvessels close to endothelial cells, mainly found associated with CNS vessels and involved in vessel formation, remodeling and stabilization.
- 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.
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Cite this page: Hill, M.A. (2020, September 28) Embryology Cardiovascular System - Blood Vessel Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Blood_Vessel_Development
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