Difference between revisions of "Talk:Cardiovascular System Development"

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PMID: 21352545
PMID: 21352545
===Maternal genome-wide DNA methylation patterns and congenital heart defects===
===Maternal genome-wide DNA methylation patterns and congenital heart defects===

Revision as of 12:19, 13 August 2011

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Cite this page: Hill, M.A. (2020, June 2) Embryology Cardiovascular System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Cardiovascular_System_Development


Prenatal cardiovascular shunts in amniotic vertebrates

Respir Physiol Neurobiol. 2011 Apr 13. [Epub ahead of print]

Dzialowski EM, Sirsat T, van der Sterren S, Villamor E. Source Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA. Abstract During amniotic vertebrate development, the embryo and fetus employ a number of cardiovascular shunts. These shunts provide a right-to-left shunt of blood and are essential components of embryonic life ensuring proper blood circulation to developing organs and fetal gas exchanger, as well as bypassing the pulmonary circuit and the unventilated, fluid filled lungs. In this review we examine and compare the embryonic shunts available for fetal mammals and embryonic reptiles, including lizards, crocodilians, and birds. These groups have either a single ductus arteriosus (mammals) or paired ductus arteriosi that provide a right-to-left shunt of right ventricular output away from the unventilated lungs. The mammalian foramen ovale and the avian atrial foramina function as a right-to-left shunt of blood between the atria. The presence of atrial shunts in non-avian reptiles is unknown. Mammals have a venous shunt, the ductus venosus that diverts umbilical venous return away from the liver and towards the inferior vena cava and foramen ovale. Reptiles do not have a ductus venosus during the latter two thirds of development. While the fetal shunts are well characterized in numerous mammalian species, much less is known about the developmental physiology of the reptilian embryonic shunts. In the last years, the reactivity and the process of closure of the ductus arteriosus have been characterized in the chicken and the emu. In contrast, much less is known about embryonic shunts in the non-avian reptiles. It is possible that the single ventricle found in lizards, snakes, and turtles and the origin of the left aorta in the crocodilians play a significant role in the right-to-left embryonic shunt in these species.

Copyright © 2011. Published by Elsevier B.V.

PMID: 21513818 http://www.ncbi.nlm.nih.gov/pubmed/21513818

Fetal cardiac dimensions at 14-40 weeks' gestation obtained using cardio-STIC-M

Ultrasound Obstet Gynecol. 2011 Feb 8. doi: 10.1002/uog.8961. [Epub ahead of print]

Luewan S, Yanase Y, Tongprasert F, Srisupundit K, Tongsong T. Source Faculty of Medicine, Department of Obstetrics and Gynecology, Chiang Mai University, Chiang Mai, Thailand. Abstract OBJECTIVES: To establish normative reference ranges of fetal cardiac dimensions derived from volume datasets acquired using spatiotemporal image correlation with M-mode display (cardio-STIC-M).

METHODS: A cross-sectional study was undertaken on singleton pregnancies with normal fetuses and accurate gestational ages. Cardio-STIC volume datasets were acquired by experienced operators using a high-resolution ultrasound machine; these were maneuvered to obtain a four chamber-view with exactly horizontal interventricular septum (IVS). Cardiac dimensions were measured in STIC-M-mode using 4D View software.

RESULTS: A total of 657 measurements, at a rate of between 15 and 37 per week, were obtained. Normal reference ranges for biventricular outer diameter, left and right ventricular inner diameter, left and right ventricular wall thickness, IVS thickness, left to right ventricular diameter ratio and left and right ventricular shortening fractions were constructed based on best-fit equations as a function of gestational age, fetal head circumference and biparietal diameter. Thirty-four volume datasets of abnormal fetal hearts were also separately assessed, many of which showed abnormal cardiac dimensions.

CONCLUSIONS: This is the first report on normal ranges of fetal cardiac dimensions constructed using the new cardio-STIC-M technology. Preliminary evaluation suggests that these reference ranges may be a useful tool in the assessment of fetal cardiac abnormalities. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

PMID: 21305637 http://www.ncbi.nlm.nih.gov/pubmed/21305637

Notch signaling regulates remodeling and vessel diameter in the extraembryonic yolk sac

BMC Dev Biol. 2011 Feb 25;11:12.

Copeland JN, Feng Y, Neradugomma NK, Fields PE, Vivian JL. Source Department of Pathology and Laboratory Medicine and Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. jvivian@kumc.edu


BACKGROUND: The signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined. Several signaling pathways, including Notch and VEGF signaling, are critical for the formation of the vasculature in the mouse. To further understand the role of Notch signaling during endothelial differentiation and the genes regulated by this pathway, both loss-of-function and gain-of-function approaches were analyzed in vivo.

RESULTS: Conditional transgenic models were used to expand and ablate Notch signaling in the early embryonic endothelium. Embryos with activated Notch1 signaling in the vasculature displayed a variety of defects, and died soon after E10.5. Most notably, the extraembryonic vasculature of the yolk sac displayed remodeling differentiation defects, with greatly enlarged lumens. These phenotypes were distinct from endothelial loss-of-function of RBPJ, a transcriptional regulator of Notch activity. Gene expression analysis of RNA isolated from the yolk sac endothelia of transgenic embryos indicated aberrant expression in a variety of genes in these models. In particular, a variety of secreted factors, including VEGF and TGF-β family members, displayed coordinate expression defects in the loss-of-function and gain-of-function models.

CONCLUSIONS: Morphological analyses of the in vivo models confirm and expand the understanding of Notch signaling in directing endothelial development, specifically in the regulation of vessel diameter in the intra- and extraembryonic vasculature. Expression analysis of these in vivo models suggests that the vascular differentiation defects may be due to the regulation of key genes through the Notch-RBPJ signaling axis. A number of these genes regulated by Notch signaling encode secreted factors, suggesting that Notch signaling may mediate remodeling and vessel diameter in the extraembryonic yolk sac via autocrine and paracrine cell communication. We propose a role for Notch signaling in elaborating the microenvironment of the nascent arteriole, suggesting novel regulatory connections between Notch signaling and other signaling pathways during endothelial differentiation.

PMID: 21352545 http://www.ncbi.nlm.nih.gov/pubmed/21352545


Maternal genome-wide DNA methylation patterns and congenital heart defects

PLoS One. 2011 Jan 24;6(1):e16506.

Chowdhury S, Erickson SW, Macleod SL, Cleves MA, Hu P, Karim MA, Hobbs CA. Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, United States of America.


The majority of congenital heart defects (CHDs) are thought to result from the interaction between multiple genetic, epigenetic, environmental, and lifestyle factors. Epigenetic mechanisms are attractive targets in the study of complex diseases because they may be altered by environmental factors and dietary interventions. We conducted a population based, case-control study of genome-wide maternal DNA methylation to determine if alterations in gene-specific methylation were associated with CHDs. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed maternal gene-specific methylation in over 27,000 CpG sites from DNA isolated from peripheral blood lymphocytes. Our study sample included 180 mothers with non-syndromic CHD-affected pregnancies (cases) and 187 mothers with unaffected pregnancies (controls). Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites, although no CpG site reached the most stringent level of genome-wide statistical significance. The majority of differentially methylated CpG sites were hypermethylated in cases and located within CpG islands. Gene Set Enrichment Analysis (GSEA) revealed that the genes of interest were enriched in multiple biological processes involved in fetal development. Associations with canonical pathways previously shown to be involved in fetal organogenesis were also observed. We present preliminary evidence that alterations in maternal DNA methylation may be associated with CHDs. Our results suggest that further studies involving maternal epigenetic patterns and CHDs are warranted. Multiple candidate processes and pathways for future study have been identified.

PMID: 21297937 http://www.ncbi.nlm.nih.gov/pubmed/21297937


Three-dimensional reconstruction imaging of the human foetal heart in the first trimester

Eur Heart J. 2010 Feb;31(4):415. Epub 2009 Dec 3.

Matsui H, Mohun T, Gardiner HM. Source Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, Queen Charlotte's and Chelsea Hospital, Du Cane Road, London W12 0HS, UK. PMID: 19965862

An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation

Proc Natl Acad Sci U S A. 2010 Oct 25. [Epub ahead of print]

Nadeau M, Georges RO, Laforest B, Yamak A, Lefebvre C, Beauregard J, Paradis P, Bruneau BG, Andelfinger G, Nemer M.

Research Unit in Cardiac Growth and Differentiation and Molecular Biology Program, Université de Montréal, Montréal, QC, Canada H3C 3J7.

Abstract In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.

PMID: 20974940 http://www.ncbi.nlm.nih.gov/pubmed/20974940


Heart Valve Development

Transcriptional Regulation of Heart Valve Progenitor Cells

PEDIATRIC CARDIOLOGY Volume 31, Number 3, 414-421, DOI: 10.1007/s00246-009-9616-x

"The development and normal function of the heart valves requires complex interactions among signaling molecules, transcription factors and structural proteins that are tightly regulated in time and space. Here we review the roles of critical transcription factors that are required for specific aspects of normal valve development. The early progenitors of the heart valves are localized in endocardial cushions that express transcription factors characteristic of mesenchyme, including Twist1, Tbx20, Msx1 and Msx2. As the valve leaflets mature, they are composed of complex stratified extracellular matrix proteins that are regulated by the transcriptional functions of NFATc1, Sox9, and Scleraxis. Each of these factors has analogous functions in differentiation of related connective tissue lineages. Together, the precise timing and localized functions of specific transcription factors control cell proliferation, differentiation, elongation, and remodeling processes that are necessary for normal valve structure and function. In addition, there is increasing evidence that these same transcription factors contribute to congenital, as well as degenerative, valve disease."

Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1


Wnt signaling in heart valve development and osteogenic gene induction

Alfieri CM, Cheek J, Chakraborty S, Yutzey KE. Dev Biol. 2010 Feb 15;338(2):127-35. Epub 2009 Dec 1. PMID: 19961844

Heart valve development: regulatory networks in development and disease. Combs MD, Yutzey KE. Circ Res. 2009 Aug 28;105(5):408-21. Review. PMID: 19713546

A new role for the human placenta as a hematopoietic site throughout gestation.


We investigated whether the human placenta contributes to embryonic and fetal hematopoietic development. Two cell populations--CD34(++)CD45(low) and CD34( +)CD45(low)--were found in chorionic villi. CD34(++) CD45(low) cells display many markers that are characteristic of multipotent primitive hematopoietic progenitors and hematopoietic stem cells. Clonogenic in vitro assays showed that CD34(++)CD45( low) cells contained colony-forming units-culture with myeloid and erythroid potential and differentiated into CD56(+) natural killer cells and CD19(+) B cells in culture. CD34(+)CD45(low) cells were mostly enriched in erythroid- and myeloid-committed progenitors. While the number of CD34(++)CD45(low) cells increased throughout gestation in parallel with placental mass. However, their density (cells per gram of tissue) reached its peak at 5 to 8 weeks, decreasing more than 7-fold from the ninth week onward. In addition to multipotent progenitors, the placenta contained intermediate progenitors, indicative of active hematopoiesis. Together, these data suggest that the human placenta is potentially an important hematopoietic organ, opening the possibility of banking placental hematopoietic stem cells along with cord blood for transplantation.


Fetal aortic arch measurements at 14 to 40 weeks' gestation derived by spatiotemporal image correlation volume data sets

J Ultrasound Med. 2009 Dec;28(12):1651-6. Udomwan P, Luewan S, Tongsong T. Source Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Abstract OBJECTIVE: The purpose of this study was to establish reference ranges for the transverse aortic arch diameter (TAD) and distal aortic isthmus diameter (DAID) in normal singleton pregnancies (14-40 weeks) based on the 3-vessel/trachea (3VT) view of cardio-spatiotemporal image correlation (STIC) volume data sets.

METHODS: A prospective descriptive study was conducted on uncomplicated singleton pregnancies with healthy fetuses and an accurate gestational age (GA). Cardio-STIC examinations were performed by experienced sonographers using a high-resolution ultrasound machine, and the volume data sets were manipulated to obtain the 3VT view and measured for the TAD and DAID.

RESULTS: A total of 554 measurements were performed, ranging from 13 to 30 for each gestational week. The best regression models were as follows: TAD (in millimeters) = -1.01 + 1.69 (GA, in weeks) (r(2) = 0.93; P < .001), and DAID (in millimeters) = -0.85 + 1.54 (GA, in weeks) (r(2) = 0.92; P < .001). A table of nomograms for 5th, 50th, and 95th percentile ranges was constructed.

CONCLUSIONS: Normative data for the TAD and DAID at each gestational week from 14 to 40 weeks were constructed by a new technique of measurement based on cardio-STIC. These reference ranges may be useful tools for assessment of fetal aortic arch abnormalities.

PMID: 19933478 http://www.ncbi.nlm.nih.gov/pubmed/19933478


  • Endothelial cell lineages of the heart. Ishii Y, Langberg J, Rosborough K, Mikawa T. Cell Tissue Res. 2009 Jan;335(1):67-73. Epub 2008 Aug 6. Review. PMID: 18682987 | PMC: 2729171

Cardiac dimensions determined by cross-sectional echocardiography in the normal human fetus from 18 weeks to term

Am J Cardiol. 1992 Dec 1;70(18):1459-67.

Tan J, Silverman NH, Hoffman JI, Villegas M, Schmidt KG. Department of Pediatrics, University of California, San Francisco 94143.


Assessment of cardiac dimensions of the chambers, great arteries and veins in the human fetus is important to distinguish abnormal dimensions from normal. This study establishes normal values based on cross-sectional echocardiographic measurements over the gestational period where these measurements may be clinically useful. Ventricular and atrial dimensions were measured from the 4-chamber view, the short-axis dimension immediately below the mitral and tricuspid valve leaflets in diastole, and the long axis from the closed apposed atrioventricular valves to their respective apices. The ventricular walls and septum were measured at the level at which cavity dimensions in diastole were measured, defining both the left and right ventricular wall thickness, as well as that of the ventricular septum. Furthermore, the long axis of the right and left atria was measured from the center of the apposed atrioventricular valve leaflets to the posterior atrial wall, and the sizes of the atrial chambers were defined using their widths at the prospective broadest points through the area of foramen ovale. From a variety of views, diameters were measured at maximal expansion of the main, left and right pulmonary arteries, the ductus arteriosus, and the superior and inferior venae cavae. The data were evaluated longitudinally from 18 weeks to term, and regression analysis was performed using the best fit of a linear or polynomial equation. The data provide a means for evaluating the normal sizes and dimensions of the fetal heart chambers, as well as the thickness of the ventricular walls and septum.

PMID: 1442619

The links in this next sections are to the original 2008 online notes pages for Cardiovascular System Development.

Cardiovascular Notes Introduction | Abnormalities | Stage 13/14 | Stage 22 | Stage 22 Selected Highpower | Heart | Heart Rate | BloodBlood Vessels | Molecular | Lymphatic | Text only page | WWW Links | Postnatal | History - Harvey

Cardiovascular Movies Heart Movies | Heart Looping | Atrial Septation | Realignment | Ventricular Septation | Heart Septation Models | Historic Heart Movie |

Other Cardiac and Vascular Movies Fetal Circulation (Before Birth) | Circulation (After Birth) | Aortic Branches to Glands (Kidneys only) | Aortic Branches to Glands (Gonads only)

Coronary Vessels

  • Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development.[1] Lie-Venema H, van den Akker NM, Bax NA, Winter EM, Maas S, Kekarainen T, Hoeben RC, deRuiter MC, Poelmann RE, Gittenberger-de Groot AC. ScientificWorldJournal. 2007 Nov 12;7:1777-98. Review. PMID: 18040540 | PDF full article
  • Cellular and molecular mechanisms of coronary vessel development.[2] Mu H, Ohashi R, Lin P, Yao Q, Chen C. Vasc Med. 2005 Feb;10(1):37-44. Review. PMID: 15920999


  • Development of innervation of coronary arteries in human foetus up until 230 mm. stage (mid-term). Br Heart J. 1970 Jan;32(1):108-13.

Smith RB.

PMID: 5417838

  • Innervation of the coronary vessels is initiated before the 30mm. stage of development.
  • All the main branches of the coronary arteries are formed and in their definitive positions by the 40 mm. stage.
  • Two plexuses have been shown for all the larger vessels after the 120 mm. stage.
  • There are coarse-fibre and fine-fibre plexuses, situated at different levels in the tunica adventitia.
  • Ganglion cells have been found in relation to the coronary arteries over the ventricles.
  • This confirms the part played by the vagal system in the innervation of the ventricle.
  • No nerve endings were seen in the tunica media.


  1. <pubmed>18040540</pubmed>
  2. <pubmed>15920999</pubmed>