Cardiovascular - Venous Development

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Heart Tube Fusion.jpg


The embryo stage 10 heart tube

Development of the heart and vascular system begins very early in mesoderm both within (embryonic) and outside (extra embryonic, yolk sac and placental) the embryo. Vascular development therefore occurs in many places, the most obvious though is the early forming heart, which grows rapidly creating an externally obvious cardiac "bulge" on the early embryo. The cardiovascular system is extensively remodelled throughout development, this current page discusses systemic venous development. Note that placental vessels are discussed in placental notes.

Eph-B4 (EPHB4; Eph receptor gene family; 7q22.1,) has been identified as an early marker of venous endothelium development[1], see also the review.[2] In the retina, angiopoietin-4 (ANGPT4) has also been identified as a factor for venous development.[3]

See also the related pages Ductus Venosus, Arterial Development, Placental Villi Blood Vessels and Coronary Circulation Development.

Historic Venous  
Historic Papers: 1902 Rabbit Inferior Vena Cava | 1909 Cervical Veins | 1925 Human Inferior Vena Cava

Historic Disclaimer - information about historic embryology pages 
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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Cardiovascular Links: cardiovascular | Heart Tutorial | Lecture - Early Vascular | Lecture - Heart | Movies | 2016 Cardiac Review | heart | coronary circulation | heart valve | heart rate | Circulation | blood | blood vessel | blood vessel histology | heart histology | Lymphatic | ductus venosus | spleen | Stage 22 | cardiovascular abnormalities | OMIM | 2012 ECHO Meeting | Category:Cardiovascular
Historic Embryology - Cardiovascular 
1902 Vena cava inferior | 1905 Brain Blood Vessels | 1909 Cervical Veins | 1909 Dorsal aorta and umbilical veins | 1912 Heart | 1912 Human Heart | 1914 Earliest Blood-Vessels | 1915 Congenital Cardiac Disease | 1915 Dura Venous Sinuses | 1916 Blood cell origin | 1916 Pars Membranacea Septi | 1919 Lower Limb Arteries | 1921 Human Brain Vascular | 1921 Spleen | 1922 Aortic-Arch System | 1922 Pig Forelimb Arteries | 1922 Chicken Pulmonary | 1923 Head Subcutaneous Plexus | 1923 Ductus Venosus | 1925 Venous Development | 1927 Stage 11 Heart | 1928 Heart Blood Flow | 1935 Aorta | 1935 Venous valves | 1938 Pars Membranacea Septi | 1938 Foramen Ovale | 1939 Atrio-Ventricular Valves | 1940 Vena cava inferior | 1940 Early Hematopoiesis | 1941 Blood Formation | 1942 Truncus and Conus Partitioning | Ziegler Heart Models | 1951 Heart Movie | 1954 Week 9 Heart | 1957 Cranial venous system | 1959 Brain Arterial Anastomoses | Historic Embryology Papers | 2012 ECHO Meeting | 2016 Cardiac Review | Historic Disclaimer

Some Recent Findings

  • Review - Molecular identity of arteries, veins, and lymphatics[2] "Arteries, veins, and lymphatic vessels are distinguished by structural differences that correspond to their different functions. Each of these vessels is also defined by specific molecular markers that persist throughout adult life; these markers are some of the molecular determinants that control the differentiation of embryonic undifferentiated cells into arteries, veins, or lymphatics. The Eph-B4 receptor and its ligand, ephrin-B2, are critical molecular determinants of vessel identity, arising on endothelial cells early in embryonic development. Eph-B4 and ephrin-B2 continue to be expressed on adult vessels and mark vessel identity. However, after vascular surgery, vessel identity can change and is marked by altered Eph-B4 and ephrin-B2 expression. Vein grafts show loss of venous identity, with less Eph-B4 expression. Arteriovenous fistulas show gain of dual arterial-venous identity, with both Eph-B4 and ephrin-B2 expression, and manipulation of Eph-B4 improves arteriovenous fistula patency. Patches used to close arteries and veins exhibit context-dependent gain of identity, that is, patches in the arterial environment gain arterial identity, whereas patches in the venous environment gain venous identity; these results show the importance of the host infiltrating cells in determining vascular identity after vascular surgery."
  • Venous Collateral Pathways in Superior Thoracic Inlet Obstruction: A Systematic Analysis of Anatomy, Embryology, and Resulting Patterns[4] "For this study, we reviewed 56 standard-of-care CT examinations over a timespan of 2 years from patients with superior thoracic inlet venous obstruction and identified eight thoracic collateral pathways for venous blood return to the right heart. We evaluated each pathway individually from an anatomic and a pathophysiologic perspective for a better understanding of how such pathways form and what patterns can be expected. ... Recognizing imaging findings associated with venous collateral pathways may prevent misdiagnosis or unnecessary follow-up examinations. Furthermore, knowledge of these collateral pathways and an understanding of the underlying cause can support interventional radiologists and vascular surgeons in planning interventional procedures and revascularization procedures."
  • Angiopoietin-4-dependent venous maturation and fluid drainage in the peripheral retina[3] "The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using genetic reporter, fate mapping, and in situ hybridization, we found Angpt4 expression in a specific sub-population of astrocytes at the site where venous morphogenesis occurs and that lower oxygen tension, which distinguishes peripheral and venous locations, enhances Angpt4 expression. Correlating with its spatiotemporal expression, deletion of Angpt4 resulted in defective venous development causing impaired venous drainage and defects in neuronal cells. In vitro characterization of angiopoietin-4 proteins revealed both ligand-specific and redundant functions among the angiopoietins. Our study identifies Angpt4 as the first growth factor for venous-specific development and its importance in venous remodeling, retinal fluid clearance and neuronal function."
More recent papers  
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This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.

  • This search now requires a manual link as the original PubMed extension has been disabled.
  • The displayed list of references do not reflect any editorial selection of material based on content or relevance.
  • References also appear on this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Venous Embryology | Vein Development | Ductus Venosus Development | Cervical Vein Development | Azygos Vein Development

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • A detailed comparison of mouse and human cardiac development[5]


Cardiac muscle histology
  • Human Embryology (2nd ed.) Larson Ch7 p151-188 Heart, Ch8 p189-228 Vasculature
  • The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Ch14: p304-349
  • Before we Are Born (5th ed.) Moore and Persaud Ch12; p241-254
  • Essentials of Human Embryology Larson Ch7 p97-122 Heart, Ch8 p123-146 Vasculature
  • Human Embryology Fitzgerald and Fitzgerald Ch13-17: p77-111

Vena Cava Development

The images below are from a historic 1925 paper by Mcclure and Butler described the development of the human vent cava using embryos from a number of human embryo collections.[6]

Infrahepatic Inferior Caval and Azygos Vein

Infrahepatic inferior caval and azygos vein formation in mammals with different degrees of mesonephric development.[7]

"Controversies regarding the development of the mammalian infrahepatic inferior caval and azygos veins arise from using topography rather than developmental origin as criteria to define venous systems and centre on veins that surround the mesonephros. We compared caudal-vein development in man with that in rodents and pigs (rudimentary and extensive mesonephric development, respectively), and used Amira 3D reconstruction and Cinema 4D-remodelling software for visualisation. The caudal cardinal veins (CCVs) were the only contributors to the inferior caval (IVC) and azygos veins. Development was comparable if temporary vessels that drain the large porcine mesonephros were taken into account. The topography of the CCVs changed concomitant with expansion of adjacent organs (lungs, meso- and metanephroi). The iliac veins arose by gradual extension of the CCVs into the caudal body region. Irrespective of the degree of mesonephric development, the infrarenal part of the IVC developed from the right CCV and the renal part from vascular sprouts of the CCVs in the mesonephros that formed 'subcardinal' veins. The azygos venous system developed from the cranial remnants of the CCVs. Temporary venous collaterals in and around the thoracic sympathetic trunk were interpreted as 'footprints' of the dorsolateral-to-ventromedial change in the local course of the intersegmental and caudal cardinal veins relative to the sympathetic trunk. Interspecies differences in timing of the same events in IVC and azygos-vein development appear to allow for proper joining of conduits for caudal venous return, whereas local changes in topography appear to accommodate efficient venous perfusion. These findings demonstrate that new systems, such as the 'supracardinal' veins, are not necessary to account for changes in the course of the main venous conduits of the embryo."

Renal Venous Development

The renal arterial and venous systems are also reorganised extensively throughout development with changing kidney position.

Embryo renal venous cartoon.jpg Adult renal venous cartoon.jpg
Embryo renal venous Adult renal venous

Links: Renal Development

Fetal Blood Flow

Fetal Blood Flow

Mean Late Fetal Blood Flows[8]

(8 subjects) in the major vessels of the human fetal circulation by phase contrast MRI. (median gestational age 37 weeks, age range of 30–39 weeks)

(left) Mean flows in ml/kg/min (right) Proportions of the combined ventricular output in the major vessels of the human fetal circulation by phase contrast MRI.
  • AAo - Ascending aorta
  • MPA - main pulmonary artery
  • DA - ductus arteriosus
  • PBF - pulmonary blood flow
  • DAo - descending aorta
  • UA - umbilical artery
  • UV - umbilical vein
  • IVC - inferior vena cava
  • SVC - superior vena cava
  • RA - right atrium
  • FO - foramen ovale
  • LA - left atrium
  • RV - right ventricle
  • LV - left ventricle
Cardiovascular Links: Fetal Blood Flow values | Mean Fetal Blood Flow | Proportions Ventricular Output | Ventricular Output (colour) | heart | blood | cardiovascular


McClure CFW. and Butler EG. The development of the vena cava inferior in man. (1925) Amer. J Anat. 35(3): 331-383.

Lewis FT. On the cervical veins and lymphatics in four human embryos, with an interpretation of anomalies on the subclavian and jugular veins in the adult. (1909)

Lewis FT. The development of the vena cava inferior. (1902) Amer. J Anat. 1(3): 229-244.


  1. Takama M & Nosoh Y. (1980). Purification and some properties of 6-phosphoglucose isomerase from Bacillus caldotenax. J. Biochem. , 87, 1821-7. PMID: 7400125 DOI.
  2. 2.0 2.1 Wolf K, Hu H, Isaji T & Dardik A. (2019). Molecular identity of arteries, veins, and lymphatics. J. Vasc. Surg. , 69, 253-262. PMID: 30154011 DOI.
  3. 3.0 3.1 Elamaa H, Kihlström M, Kapiainen E, Kaakinen M, Miinalainen I, Ragauskas S, Cerrada-Gimenez M, Mering S, Nätynki M & Eklund L. (2018). Angiopoietin-4-dependent venous maturation and fluid drainage in the peripheral retina. Elife , 7, . PMID: 30444491 DOI.
  4. Meier A & Alkadhi H. (2019). Venous Collateral Pathways in Superior Thoracic Inlet Obstruction: A Systematic Analysis of Anatomy, Embryology, and Resulting Patterns. AJR Am J Roentgenol , , 1-11. PMID: 31039029 DOI.
  5. Krishnan A, Samtani R, Dhanantwari P, Lee E, Yamada S, Shiota K, Donofrio MT, Leatherbury L & Lo CW. (2014). A detailed comparison of mouse and human cardiac development. Pediatr. Res. , 76, 500-7. PMID: 25167202 DOI.
  6. McClure CFW. and Butler EG. The development of the vena cava inferior in man. (1925) Amer. J Anat. 35(3): 331-383.
  7. Hikspoors JP, Mekonen HK, Mommen GM, Cornillie P, Köhler SE & Lamers WH. (2016). Infrahepatic inferior caval and azygos vein formation in mammals with different degrees of mesonephric development. J. Anat. , 228, 495-510. PMID: 26659476 DOI.
  8. Seed M, van Amerom JF, Yoo SJ, Al Nafisi B, Grosse-Wortmann L, Jaeggi E, Jansz MS & Macgowan CK. (2012). Feasibility of quantification of the distribution of blood flow in the normal human fetal circulation using CMR: a cross-sectional study. J Cardiovasc Magn Reson , 14, 79. PMID: 23181717 DOI.


Nigro B & Ayarragaray JEF. (2021). Anomalies of Inferior Vena Cava: Implications and Considerations in Retroperitoneal Surgical Procedures. Ann Vasc Surg , , . PMID: 34644626 DOI.

Kelly RG. (2012). The second heart field. Curr. Top. Dev. Biol. , 100, 33-65. PMID: 22449840 DOI.

Carmeliet P & Jain RK. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature , 473, 298-307. PMID: 21593862 DOI.

Degani S. (2008). Fetal cerebrovascular circulation: a review of prenatal ultrasound assessment. Gynecol. Obstet. Invest. , 66, 184-96. PMID: 18607112 DOI.

Tchirikov M, Schröder HJ & Hecher K. (2006). Ductus venosus shunting in the fetal venous circulation: regulatory mechanisms, diagnostic methods and medical importance. Ultrasound Obstet Gynecol , 27, 452-61. PMID: 16565980 DOI.

Kiserud T. (2005). Physiology of the fetal circulation. Semin Fetal Neonatal Med , 10, 493-503. PMID: 16236564 DOI.

Kiserud T & Acharya G. (2004). The fetal circulation. Prenat. Diagn. , 24, 1049-59. PMID: 15614842 DOI.


Jiji RS & Kramer CM. (2011). Cardiovascular magnetic resonance: applications in daily practice. Cardiol Rev , 19, 246-54. PMID: 21808168 DOI.

Ribatti D & Djonov V. (2011). Angiogenesis in development and cancer today. Int. J. Dev. Biol. , 55, 343-4. PMID: 21732277 DOI.

Cammarato A, Ahrens CH, Alayari NN, Qeli E, Rucker J, Reedy MC, Zmasek CM, Gucek M, Cole RN, Van Eyk JE, Bodmer R, O'Rourke B, Bernstein SI & Foster DB. (2011). A mighty small heart: the cardiac proteome of adult Drosophila melanogaster. PLoS ONE , 6, e18497. PMID: 21541028 DOI.

Min JK, Park H, Choi HJ, Kim Y, Pyun BJ, Agrawal V, Song BW, Jeon J, Maeng YS, Rho SS, Shim S, Chai JH, Koo BK, Hong HJ, Yun CO, Choi C, Kim YM, Hwang KC & Kwon YG. (2011). The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells. J. Clin. Invest. , 121, 1882-93. PMID: 21540552 DOI.

Guo C, Sun Y, Zhou B, Adam RM, Li X, Pu WT, Morrow BE, Moon A & Li X. (2011). A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. J. Clin. Invest. , 121, 1585-95. PMID: 21364285 DOI.

Arráez-Aybar LA, Turrero-Nogués A & Marantos-Gamarra DG. (2008). Embryonic cardiac morphometry in Carnegie stages 15-23, from the Complutense University of Madrid Institute of Embryology Human Embryo Collection. Cells Tissues Organs (Print) , 187, 211-20. PMID: 18057862 DOI.

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Additional Images


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Ziegler Models

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Cardiovascular Terms  
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. (2024, June 23) Embryology Cardiovascular - Venous Development. Retrieved from

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