Cardiovascular System - Blood Vessel Development
Introduction
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!
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.
Some Recent Findings
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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.
Endothelial Tube Formation
Vessel Specification
The following data is from a recent review.[1]
- Arterial specification - vascular endothelial growth factor (VEGF) induces expression of Notch signaling genes (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.
- Venous specification - orphan nuclear receptor COUP-TFII is a determinant factor by inhibiting expression of arterial specific genes, including Nrp1 and Notch.
- Lymphatic specification - subpopulation of venous endothelial cells acquire lymphatic endothelial cell fate by progressively expressing the transcription factors Sox18 and Prox1.
Arterial identity
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. |
- Compiled data[1]
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.
Links: OMIM - VEGFA | OMIM - Notch
Regulators of Growth
The following data is from a review article on ovary vascular development.[5]
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
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.
(Text modified from: [6])
References
<pubmed>10948449</pubmed> <pubmed>12406884</pubmed>
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Blood Vessel Development Terms
- angioblasts stem cells in blood islands generating endothelial cells
- angiogenesis the formation of blood vessels also called vasculogenesis in the embryo
- blood islands earliest sites of blood vessel and blood cell formation, seen mainly on yolk sac chorion
- vascular endothelial growth factor (VEGF) protein growth factor family that stimulates blood vessel growth, a similar factor can be found in the placenta (PIGF).
Glossary Links
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Cite this page: Hill, M.A. (2024, June 15) Embryology Cardiovascular System - Blood Vessel Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Blood_Vessel_Development
- © Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G