Talk:Cardiovascular System - Blood Vessel Development

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Cite this page: Hill, M.A. (2024, June 12) Embryology Cardiovascular System - Blood Vessel Development. Retrieved from


Blatchley MR & Gerecht S. (2019). Reconstructing the Vascular Developmental Milieu In Vitro. Trends Cell Biol. , , . PMID: 31718894 DOI. Reconstructing the Vascular Developmental Milieu In Vitro.

Abstract Understanding human development has fascinated scientists for centuries. With advancements in stem cell technologies, this understanding has expanded beyond fascination to application towards informing the design of therapeutics in regenerative medicine. A focus on establishing a better grasp of the physicochemical cues governing differentiation and tissue assembly has continually enhanced engineered systems to an unprecedented level of biomimicry and, in doing so, has allowed the design of novel therapeutics. The vasculature has a critical role during early stages of development and regeneration events, and is responsive to a range of dynamic environmental cues. In this review, we present biomaterials systems capable of spatially and temporally controlling environmental signals that guide vascular fate and assembly, thereby further informing our understanding of differentiation schema. Copyright © 2019 Elsevier Ltd. All rights reserved.

KEYWORDS: biomaterials; endothelial cells; extracellular matrix; hydrogels; hypoxia; shear; stem cells; vascular development PMID: 31718894 DOI: 10.1016/j.tcb.2019.10.004

Molecular identity of arteries, veins, and lymphatics

J Vasc Surg. 2019 Jan;69(1):253-262. doi: 10.1016/j.jvs.2018.06.195. Epub 2018 Aug 25.

Wolf K1, Hu H1, Isaji T1, Dardik A2.

Vascular Biology and Therapeutics Program and Department of Surgery, Yale University School of Medicine, New Haven, Conn. 2 Vascular Biology and Therapeutics Program and Department of Surgery, Yale University School of Medicine, New Haven, Conn; VA Connecticut Healthcare System, West Haven, Conn. Electronic address: Abstract BACKGROUND: 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. METHODS: This is a review of experimental literature. RESULTS: 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. CONCLUSIONS: Changes in the vessel's molecular identity after vascular surgery correspond to structural changes that depend on the host's postsurgical environment. Regulation of vascular identity and the underlying molecular mechanisms may allow new therapeutic approaches to improve vascular surgical procedures. Published by Elsevier Inc.

KEYWORDS: Angiogenesis; Arteriogenesis; Eph-B4; Ephrin-B2; Identity; Vasculogenesis PMID: 30154011 PMCID: PMC6309638 [Available on 2020-01-01] DOI: 10.1016/j.jvs.2018.06.195


Erythro-myeloid progenitors can differentiate from endothelial cells and modulate embryonic vascular remodeling

Sci Rep. 2017 Mar 8;7:43817. doi: 10.1038/srep43817.

Kasaai B1,2, Caolo V1, Peacock HM1, Lehoux S3, Gomez-Perdiguero E4, Luttun A1, Jones EA1.

Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do. When the endothelium is labelled with AcLDL before EMPs differentiate, EMPs and EMP-derived cells arise that are AcLDL+. If AcLDL is injected after the onset of EMP differentiation, however, the majority of EMP-derived cells are not double labelled. We find that cell division precedes entry of EMPs into circulation, and that blood flow facilitates the transition of EMPs from the endothelium into circulation in a nitric oxide-dependent manner. In gain-of-function studies, we inject the CSF1-Fc ligand in embryos and found that this increases the number of CSF1R+ cells, which localize to the venous plexus and significantly disrupt venous remodeling. This is the first study to definitively establish that EMPs arise from the endothelium in vivo and show a role for early myeloid cells in vascular development. PMID: 28272478 PMCID: PMC5341067 DOI: 10.1038/srep43817

Is cerebroplacental ratio a marker of impaired fetal growth velocity and adverse pregnancy outcome?

Am J Obstet Gynecol. 2017 Jun;216(6):606.e1-606.e10. doi: 10.1016/j.ajog.2017.02.005. Epub 2017 Feb 8.

Khalil A1, Morales-Rosello J2, Khan N2, Nath M3, Agarwal P2, Bhide A2, Papageorghiou A2, Thilaganathan B2.


BACKGROUND: The cerebroplacental ratio has been proposed as a marker of failure to reach growth potential near term. Low cerebroplacental ratio, regardless of the fetal size, is independently associated with the need for operative delivery for presumed fetal compromise and with neonatal unit admission at term. OBJECTIVE: The main aim of this study was to evaluate whether the cerebroplacental ratio at term is a marker of reduced fetal growth rate. The secondary aim was to investigate the relationship between a low cerebroplacental ratio at term, reduced fetal growth velocity, and adverse pregnancy outcome. STUDY DESIGN: This was a retrospective cohort study of singleton pregnancies in a tertiary referral center. The abdominal circumference was measured at 20-24 weeks' gestation and both abdominal circumference and fetal Dopplers recorded at or beyond 35 weeks, within 2 weeks of delivery. Abdominal circumference and birthweight values were converted into Z scores and centiles, respectively, and fetal Doppler parameters into multiples of median, adjusting for gestational age. Abdominal circumference growth velocity was quantified using the difference in the abdominal circumference Z score, comparing the scan at or beyond 35 weeks with the scan at 20-24 weeks. Both univariable and multivariable logistic regression analyses were performed to investigate the association between low cerebroplacental ratio and the low abdominal circumference growth velocity (in the lowest decile) and to identify and adjust for potential confounders. As a sensitivity analysis, we refitted the model excluding the data on pregnancies with small-for-gestational-age neonates. RESULTS: The study included 7944 pregnancies. Low cerebroplacental ratio multiples of median was significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 2.10; 95% confidence interval, 1.71-2.57, P <0.001) and small for gestational age (adjusted odds ratio, 3.60; 95% confidence interval, 3.04-4.25, P < .001). After the exclusion of pregnancies resulting in small-for-gestational-age neonates, a low cerebroplacental ratio multiples of the median remained significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 1.76; 95% confidence interval, 1.34-2.30, P < .001) and birthweight centile (adjusted odds ratio, 0.99; 95% confidence interval, 0.998-0.995, P < .001). The need for operative delivery for fetal compromise was significantly associated with a low cerebroplacental ratio (adjusted odds ratio, 1.40; 95% confidence interval, 1.10-1.78, P = .006), even after adjusting for both the umbilical artery pulsatility index multiples of the median and middle cerebral artery pulsatility index multiples of median. The results were similar, even after the exclusion of pregnancies resulting in small-for-gestational-age neonates (adjusted odds ratio, 1.39; 95% confidence interval, 1.06-1.84, P = .018). Low cerebroplacental ratio multiples of the median remained significantly associated with the risk of operative delivery for presumed fetal compromise (P < .001), even after adjusting for the known antenatal and intrapartum risk factors. These associations persisted, even after the exclusion of small-for-gestational-age births. In appropriate-for-gestational-age-sized fetuses, abdominal circumference growth velocity was significantly lower in those with a low cerebroplacental ratio multiples of the median than in those with normal cerebroplacental ratio multiples of the median (P < .001). CONCLUSION: The cerebroplacental ratio is a marker of impaired fetal growth velocity and adverse pregnancy outcome, even in fetuses whose size is considered appropriate using conventional biometry. Copyright © 2017 Elsevier Inc. All rights reserved. KEYWORDS: abdominal circumference; adverse pregnancy outcome; birthweight; cerebroplacental ratio; fetal growth restriction; growth velocity; impaired; lowest decile; second trimester; small for gestational age; third trimester PMID: 28189607 DOI: 10.1016/j.ajog.2017.02.005 [Indexed for MEDLINE]


The relationship between human placental morphometry and ultrasonic measurements of utero-placental blood flow and fetal growth

Placenta. 2016 Feb;38:41-8. doi: 10.1016/j.placenta.2015.12.003. Epub 2015 Dec 12.

Salavati N1, Sovio U2, Mayo RP3, Charnock-Jones DS4, Smith GC5.


INTRODUCTION: Ultrasonic fetal biometry and arterial Doppler flow velocimetry are widely used to assess the risk of pregnancy complications. There is an extensive literature on the relationship between pregnancy outcomes and the size and shape of the placenta. However, ultrasonic fetal biometry and arterial Doppler flow velocimetry have not previously been studied in relation to postnatal placental morphometry in detail. METHODS: We conducted a prospective cohort study of nulliparous women in The Rosie Hospital, Cambridge (UK). We studied a group of 2120 women who had complete data on uterine and umbilical Doppler velocimetry and fetal biometry at 20, 28 and 36 weeks' gestational age, digital images of the placenta available, and delivered a liveborn infant at term. Associations were expressed as the difference in the standard deviation (SD) score of the gestational age adjusted ultrasound measurement (z-score) comparing the lowest and highest decile of the given placental morphometric measurement. RESULTS: The lowest decile of placental surface area was associated with 0.87 SD higher uterine artery Doppler mean pulsatility index (PI) at 20 weeks (95% CI: 0.68 to 1.07, P < 0.001). The lowest decile of placental weight was associated with 0.73 SD higher umbilical artery Doppler PI at 36 weeks (95% CI: 0.54 to 0.93, P < 0.001). The lowest decile of both placental weight and placental area were associated with reduced growth velocity of the fetal abdominal circumference between 20 and 36 weeks (both P < 0.001). CONCLUSION: Placental area and weight are associated with uterine and umbilical blood flow, respectively, and both are associated with fetal growth rate. Copyright © 2015 Elsevier Ltd. All rights reserved. KEYWORDS: Doppler flow velocimetry; Fetal growth; Human; Morphometry; Placenta PMID: 26907381 DOI: 10.1016/j.placenta.2015.12.003


J Anat. 2015 Sep;227(3):286-96. doi: 10.1111/joa.12347. Epub 2015 Jul 16.

Quantitative comparison of cerebral artery development in human embryos with other eutherians

Ashwell KW1, Shulruf B2. Author information Abstract The embryonic and early fetal human brain is known to undergo extraordinary expansion of its cellular population during embryonic and early fetal life, and is critically dependant on a steady supply of nutrients and oxygen for proper brain development. Quantitative analysis of the internal radius of the aorta and cerebral arteries in a range of eutherian mammals has been used to compare arterial flow to the developing human brain with that to the brains of non-human eutherians. Human embryos showed a much steeper rise of internal radius of the aorta with increasing body size than the embryos of non-human eutherians, but the thickness of the aorta rose at the same pace relative to body size in both humans and non-humans, suggesting that aortic pressure is similar in all eutherian embryos of a similar size. The sums of internal radii of both the internal carotids and vertebral arteries of human embryos raised to the fourth power were much lower at embryonic stages (less than 22 mm body length) than in non-human eutherians, were similar between humans and non-humans at 22-30 mm body length, and exceeded the non-humans at body lengths of more than 30 mm. The relative size of the internal calibre of the cerebral feeder arteries (internal carotid and vertebral) to the aorta did not change between embryonic and fetal sizes in either humans or non-humans. The findings suggest that the developing human brain may actually receive less blood flow at embryonic sizes (less than 22 mm body length) than do other mammalian embryos of a similar body size, but that internal carotid and vertebral flow is higher in human fetuses (body length greater than 30 mm) than in developing non-humans of the same body size. Increased flow to the developing human brain relative to non-humans is achieved by simultaneous increases in both aortic and cerebral feeder artery internal calibre. KEYWORDS: Poiseuille's law; aorta; cerebral cortex; cerebral metabolism; cortical plate; proliferative zones PMID: 26183939 PMCID: PMC4560563 DOI: 10.1111/joa.12347

The alternative splicing factor Nova2 regulates vascular development and lumen formation

Nat Commun. 2015 Oct 8;6:8479. doi: 10.1038/ncomms9479.

Giampietro C1,2, Deflorian G1, Gallo S3,4, Di Matteo A3,5, Pradella D3,5, Bonomi S3, Belloni E3, Nyqvist D6, Quaranta V3, Confalonieri S1,7, Bertalot G7, Orsenigo F1, Pisati F1, Ferrero E8, Biamonti G3, Fredrickx E9, Taveggia C9, Wyatt CD10,11, Irimia M10,11, Di Fiore PP1,7,12, Blencowe BJ13, Dejana E1,2,14, Ghigna C3. Author information Abstract Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.

PMID 26446569

A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood Supply

J Stroke. 2015 May;17(2):144-58. doi: 10.5853/jos.2015.17.2.144. Epub 2015 May 29.

Menshawi K1, Mohr JP1, Gutierrez J1.


The anatomy of the arterial system supplying blood to the brain can influence the development of arterial disease such as aneurysms, dolichoectasia and atherosclerosis. As the arteries supplying blood to the brain develop during embryogenesis, variation in their anatomy may occur and this variation may influence the development of arterial disease. Angiogenesis, which occurs mainly by sprouting of parent arteries, is the first stage at which variations can occur. At day 24 of embryological life, the internal carotid artery is the first artery to form and it provides all the blood required by the primitive brain. As the occipital region, brain stem and cerebellum enlarge; the internal carotid supply becomes insufficient, triggering the development of the posterior circulation. At this stage, the posterior circulation consists of a primitive mesh of arterial networks that originate from projection of penetrators from the distal carotid artery and more proximally from carotid-vertebrobasilar anastomoses. These anastomoses regress when the basilar artery and the vertebral arteries become independent from the internal carotid artery, but their persistence is not uncommon in adults (e.g., persistent trigeminal artery). Other common remnants of embryological development include fenestration or duplication (most commonly of the basilar artery), hypoplasia (typically of the posterior communicating artery) or agenesis (typically of the anterior communicating artery). Learning more about the hemodynamic consequence that these variants may have on the brain territories they supply may help understand better the underlying physiopathology of cerebral arterial remodeling and stroke in patients with these variants. KEYWORDS: Arterial variants; Cerebral arteries; Circle of willis; Embryology; Remodeling; Stroke

PMID 26060802

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Molecular Regulation of Arteriovenous Specification and Maintenance

Dev Dyn. 2015 Jan 14. doi: 10.1002/dvdy.24252. [Epub ahead of print]

Fish JE1, Wythe JD.


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. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc. KEYWORDS: ETS; Notch; Vegf; artery; vasculogenesis; vein PMID 25641373


Embryonic origins of human vascular smooth muscle cells: implications for in vitro modeling and clinical application

Cell Mol Life Sci. 2014 Jun;71(12):2271-88. doi: 10.1007/s00018-013-1554-3. Epub 2014 Jan 18.

Sinha S1, Iyer D, Granata A.


Vascular smooth muscle cells (SMCs) arise from multiple origins during development, raising the possibility that differences in embryological origins between SMCs could contribute to site-specific localization of vascular diseases. In this review, we first examine the developmental pathways and embryological origins of vascular SMCs and then discuss in vitro strategies for deriving SMCs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We then review in detail the potential for vascular disease modeling using iPSC-derived SMCs and consider the pathological implications of heterogeneous embryonic origins. Finally, we touch upon the role of human ESC-derived SMCs in therapeutic revascularization and the challenges remaining before regenerative medicine using ESC- or iPSC-derived cells comes of age.

PMID 24442477


Time-lapse microscopy of macrophages during embryonic vascular development

Dev Dyn. 2012 Jul 19. doi: 10.1002/dvdy.23835.

Al-Roubaie S, Hughes JH, Filla MB, Lansford R, Lehoux S, Jones EA. Source Department of Chemical Engineering, McGill University, 3610 University St, Montreal, QC, Canada, H3A 2B2.


BACKGROUND: Macrophages are present before the onset of blood flow but very little is known about their function in vascular development. We have developed a technique to concurrently label both endothelial cells and macrophages for time-lapse microscopy using co-injection of fluorescently-conjugated acetylated low-density-lipoprotein (AcLDL) and phagocytic dye PKH26-PCL. RESULTS: We characterize double-labeled cells to confirm specific labeling of macrophages. Double-labeled cells circulate, roll along the endothelium, and extravasate from vessels. Most observed macrophages are integrated into the vessel wall, showing an endothelial-like morphology. We used transgenic quail that express a fluorescent protein driven by the endothelial-specific promoter Tie1 in conjugation with the phagocytic dye to analyze these cells. Circulating PKH26-PCL labeled cells are mostly Tie1- but those which have integrated into the vessel wall are largely Tie1+. The endothelial-like phagocytic cells were generally stationary during normal vascular development. We therefore induced vascular remodeling and found that these cells could be recruited to sites of remodeling. CONCLUSIONS: The active interaction of endothelial cells and macrophages support the hypothesis that these cells are involved in vascular remodelling. The presence of phagocytic endothelial-like cells suggests either a myeloid-origin to certain endothelial cells or that circulating endothelial cells/hematopoietic stem cells have phagocytic capacity. Copyright © 2012 Wiley Periodicals, Inc.

PMID 22815139

Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling

Proc Natl Acad Sci U S A. 2012 May 1;109(18):6993-6998. Epub 2012 Apr 16.

Chang L, Noseda M, Higginson M, Ly M, Patenaude A, Fuller M, Kyle AH, Minchinton AI, Puri MC, Dumont DJ, Karsan A. Source Genome Sciences Centre, Integrative Oncology Department, and Cancer Genetics Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3.


Vascular smooth muscle cells (VSMC) have been suggested to arise from various developmental sources during embryogenesis, depending on the vascular bed. However, evidence also points to a common subpopulation of vascular progenitor cells predisposed to VSMC fate in the embryo. In the present study, we use binary transgenic reporter mice to identify a Tie1(+)CD31(dim)vascular endothelial (VE)-cadherin(-)CD45(-) precursor that gives rise to VSMC in vivo in all vascular beds examined. This precursor does not represent a mature endothelial cell, because a VE-cadherin promoter-driven reporter shows no expression in VSMC during murine development. Blockade of Notch signaling in the Tie1(+) precursor cell, but not the VE-cadherin(+) endothelial cell, decreases VSMC investment of developing arteries, leading to localized hemorrhage in the embryo at the time of vascular maturation. However, Notch signaling is not required in the Tie1(+) precursor after establishment of a stable artery. Thus, Notch activity is required in the differentiation of a Tie1(+) local precursor to VSMC in a spatiotemporal fashion across all vascular beds.

PMID 22509029

Life is a pattern: vascular assembly within the embryo

Front Biosci (Elite Ed). 2012 Jan 1;4:2269-88.

Heinke J, Patterson C, Moser M. Source Department of Internal Medicine III, University of Freiburg, Germany.


The formation of the vascular system is one of the earliest and most important events during organogenesis in the developing embryo because the growing organism needs a transportation system to supply oxygen and nutrients and to remove waste products. Two distinct processes termed vasculogenesis and angiogenesis lead to a complex vasculature covering the entire body. Several cellular mechanisms including migration, proliferation, differentiation and maturation are involved in generating this hierarchical vascular tree. To achieve this aim, a multitude of signaling pathways need to be activated and coordinated in spatio-temporal patterns. Understanding embryonic molecular mechanism in angiogenesis further provides insight for therapeutic approaches in pathological conditions like cancer or ischemic diseases in the adult. In this review, we describe the current understanding of major signaling pathways that are necessary and active during vascular development.

PMID 22202036


Specification of arterial, venous, and lymphatic endothelial cells during embryonic development

Kume T. Histol Histopathol. 2010 May;25(5):637-46. Review.

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. Therefore, it has now evident that arterial-venous cell fate determination and subsequent lymphatic development are regulated by the multi-step regulatory system associated with the key signaling pathways and transcription factors. Furthermore, new signaling molecules as additional regulators in these processes have recently been identified. As the mechanistic basis for a link between signaling pathways and transcriptional networks in arterial, venous and lymphatic endothelial cells begins to be uncovered, it is now time to summarize the literature on this exciting topic and provide perspectives for future research in the field.

PMID 20238301

Fetal anatomy of the human carotid sheath and structures in and around it

Anat Rec (Hoboken). 2010 Mar;293(3):438-45.

Miyake N, Hayashi S, Kawase T, Cho BH, Murakami G, Fujimiya M, Kitano H.

Department of Otorhinolaryngology, Tottori University, Yonago, Japan. Abstract The aim of this study was to find basic rules governing the morphological development of the typical neurovascular sheath. We carried out histological examination of 15 paraffin-embedded mid-term fetuses at 9-25 weeks of gestation (three fetuses each at 9, 12, 15, 20, and 25 weeks). As the result, the vagus nerve showed a high propensity to change its topographical relationship with the common carotid artery (CCA) during 9-20 weeks of gestation: that is, from a primitive ventral course to a final dorsal course. The adventitia of the great arteries, which was distinct from other fascial structures, became evident by 15 weeks. The carotid sheath appeared at and after 20 weeks: it was clearly separated from the prevertebral lamina of the deep cervical fasciae, but fused with the pretracheal lamina covering the strap muscles. Thus the carotid sheath, as well as the topographical relationships of structures within it, seems to become established much later than the prevertebral and pretracheal laminae of the deep cervical fasciae. However, the adventitia of the cervical great arteries consistently becomes evident much earlier than the sheath, and it seems to be regarded as one of the basic components of the fetal deep cervical fasciae.

PMID 20169562

<pubmed>17259973</pubmed>"In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. ...suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns."

<pubmed>16799567</pubmed>"More than 25 years ago, in some of the first endothelial cell culture experiments in vitro, Folkman and Haudenschild described "longitudinal vacuoles" that "appeared to be extruded and connected from one cell to the next" "...Here we use high-resolution time-lapse two-photon imaging of transgenic zebrafish to examine how endothelial tubes assemble in vivo, comparing our results with time-lapse imaging of human endothelial-cell tube formation in three-dimensional collagen matrices in vitro. Our results provide strong support for a model in which the formation and intracellular and intercellular fusion of endothelial vacuoles drives vascular lumen formation."



Sonic hedgehog is required for the assembly and remodeling of branchial arch blood vessels

Dev Dyn. 2008 Jul;237(7):1923-34.

Kolesová H, Roelink H, Grim M. Source Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Prague, Czech Republic.


Sonic hedgehog (Shh) is a morphogen involved in many developmental processes. Injection of cells (5E1) that produce a Shh-blocking antibody causes an attenuation of the Shh response, and this causes vascular malformations and impaired remodeling characterized by hemorrhages and protrusions of the anterior cardinal vein and outflow tract, delayed fusion of the dorsal aortae, impaired branching of the internal carotid artery, and delayed remodeling of the aortic arches. Distribution of smooth muscle cells in the vessel wall is unchanged. In 5E1-injected embryos, we also observed impaired assembly of endothelial cells into vascular tubes, particularly in the sixth branchial arch, around the anterior cardinal vein and around the dorsal aorta. In 5E1-treated embryos, increased numbers of macrophage-like cells, apoptotic cells, and a decreased level of proliferation were observed in head mesenchyme. Together, these observations show that Shh signaling is required at multiple stages for proper vessel formation and remodeling.

PMID 18570256

Morphometric and volumetric analysis of the middle cerebral artery in human fetuses

Acta Neurobiol Exp (Wars). 2009;69(1):129-37.

Gielecki J, Zurada A, Kozłowska H, Nowak D, Loukas M. Source Department of Anatomy, Medical Faculty of the University of Warmia and Masuria, Olsztyn, Poland.


The morphometrical and volumetrical changes of the middle cerebral artery (MCA) during the fetal period of development were analyzed by digital-image analysis system (DIAS). Examinations were performed on 304 MCAs from 152 brains of human fetuses ranging from the 12th to 40th weeks of gestation. MCAs were analyzed with respect to its branching from the internal carotid artery and its division into the main cortical branches. No statistically significant differences were found between the mean values of the diameter, length and volume of the left and right M1 segments of the MCAs in all studied age groups.

PMID 19325646


Origin, differentiation, and maturation of human pulmonary veins

Am J Respir Cell Mol Biol. 2002 Mar;26(3):333-40.

Hall SM, Hislop AA, Haworth SG.

Unit of Vascular Biology and Pharmacology, Institute of Child Health, University College, London, United Kingdom. Abstract Recent studies on human embryonic and fetal lungs show that the pulmonary arteries form by vasculogenesis. Little is known of the early development of the pulmonary veins. Using immunohistochemical techniques and serial reconstruction, we studied 18 fetal and neonatal lungs. Sections were stained with antibodies specific for endothelium (CD31, von Willebrand factor) and smooth muscle (alpha and gamma smooth muscle actin, smooth muscle myosin, calponin, caldesmon, and desmin) and antibodies specific for the matrix glycoprotein tenascin, the receptor protein tyrosine kinase EphB4, and its ligand ephrinB2. Kiel University-raised antibody number 67 (Ki67) expression allowed qualitative assessment of cell replication. By 34 d gestation, there was continuity between the aortic sac, pulmonary arteries, capillaries, pulmonary veins, and atrium. The pulmonary veins formed by vasculogenesis in the mesenchyme surrounding the terminal buds during the pseudoglandular period and probably by angiogenesis in the canalicular and alveolar stages. EphB4 and ephrinB2 did not distinguish between presumptive venous and arterial endothelium as they do in mouse. All venous smooth muscle cells derived directly from the mesenchyme, gradually acquiring smooth muscle specific proteins from 56 d gestation. Thus, both pulmonary arteries and veins arise by vasculogenesis, but the origins of their smooth muscle cells and their cytoskeletal protein content are different.

PMID 11867341


Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation

Am J Respir Cell Mol Biol. 2000 Aug;23(2):194-203.

Hall SM, Hislop AA, Pierce CM, Haworth SG.

Unit of Vascular Biology and Pharmacology, Cardiovascular and Respiratory Sciences, Institute of Child Health, University College of London, London, United Kingdom.

Abstract Recent studies on the morphogenesis of the pulmonary arteries have focused on nonhuman species such as the chick and the mouse. Using immunohistochemical techniques, we have studied 16 lungs from human embryos and fetuses from 28 d of gestation to newborn, using serial sections stained with a panel of antibodies specific for endothelium, smooth muscle, and extracellular matrix proteins. Cell replication was also assessed. Serial reconstruction showed a continuity of circulation between the heart and the capillary plexus from at least 38 d of gestation. The intrapulmonary arteries appeared to be derived from a continuous expansion of the primary capillary plexus that is from within the mesenchyme, by vasculogenesis. The arteries formed by continuous coalescence of endothelial tubes alongside the newly formed airway. Findings were consistent with the pulmonary arterial smooth muscle cells being derived from three sites in a temporally distinct sequence: the earliest from the bronchial smooth muscle, later from the mesenchyme surrounding the arteries, and last from the endothelial cells. Despite their different origins, all smooth muscle cells followed the same sequence of expression of smooth muscle-specific cytoskeletal proteins with increasing age. The order of appearance of these maturing proteins was from the subendothelial cells outward across the vessel wall and from hilum to periphery. The airways would seem to act as a template for pulmonary artery development. This study provides a framework for studying the signaling mechanisms controlling the various aspects of lung development.

intrapulmonary arteries

  • appeared to be derived from a continuous expansion of the primary capillary plexus from within the mesenchyme, by vasculogenesis.
  • arteries formed by continuous coalescence of endothelial tubes alongside the newly formed airway.

pulmonary arterial smooth muscle cells derived from three sites in a temporally distinct sequence

  1. earliest from the bronchial smooth muscle
  2. from the mesenchyme surrounding the arteries
  3. last from the endothelial cells.
  • all smooth muscle cells followed the same sequence of expression of smooth muscle-specific cytoskeletal proteins with increasing age.
  • order of appearance of these maturing proteins was from the subendothelial cells outward across the vessel wall and from hilum to periphery.

The airways would seem to act as a template for pulmonary artery development.

PMID 10919986

  1. <pubmed>16794034</pubmed>