Cardiovascular Development - University of Pennsylvaniadove.med.upenn.edu/~dawei/DB2013/blood-heart-vascular-handout-2… · 2. outline the fusion of the cardiac tube to form the

Cardiovascular Development

Handout for “Developmental Biology”

Dawei W Dong

Learning goals

1. explain the early development of the cardiac tube from visceral mesoderm ahead of the

neural plate which is then folded beneath the pharynx of the head fold.

2. outline the fusion of the cardiac tube to form the simple linear heart, the segmentation

and the loop formation with sinus venosus, atrium, ventricle, bulbus cordis, and truncus

arteriosus.

3. show how septum formation in the primitive heart allows separate pumping of blood into

the aortic and the pulmonary trunk.

4. describe the heart inlet separation through the incorporation of the sinus venosus and the

pulmonary veins into the atrium.

5. understand the developmental process by which the conus cordis and truncus arteriosus

are adapted to give the aortic and pulmonary trunk, i.e., the heart outlet separation.

6. describe the three periods of blood cell formation related to the yolk sac, the liver and

the bone marrow.

7. define the three circulatory arcs of the heart to/from the body tissues, the yolk sac

(vitelline) and the allantois (umbilical), describe their functions, and understand devel-

opmental changes of the arterial and venous systems, in particular, the left and right

symmetry breaking.

8. understand the changes of the circulation at birth.

Quiz

Please test yourself with the quizzes at the end. It does not cover everything, but should

give you some hints at how well you have learned the subject.

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Cardiovascular Development Dawei W Dong

1 Formation and folding of the cardiac tube

The cardiac development is specified through BMP signalling originating from the under-

lying hypoblast and endoderm. Inhibitory signals from the neural tube (Wnt) prevent the

formation of cardiogenic fields in the posterior parts of the embryo. In the anterior portion of

the embryo, on the contrary, hypoblast and endodermal cells within the developing foregut

produce signalling molecules antagonizing the neural tube Wnt signalling, thus enable the

cardiac development.

The cardiac tube is horsedshoe-shaped and is established in the early gastrula from

regions of haemangioblasts in the visceral mesoderm (the cardiogenic field) ahead of the

embryo itself (Figure 1). As a result of the head fold, the developing heart ends up beneath

the gut tube (Figure 2, 3), the posterior extensions of the tube become anterior and develop

into the two ventral aortae, and the anterior of the cardiac tube becomes posterior and fuses

with the vitelline veins (Figure 4).

The two dorsal aortae form independently from clusters of angioblasts assembled on each

side of the midline of the embryo, outside the cardiogenic field. They grow cranial-ventrally

to meet the ventral aortae through aortic arches, while fuse caudally.

Due to the lateral folding, the posterior portions of the two ventral aortae fuse to produce

a single tube. The two ventral aortae connect the anterior end of the tube, the outlet of the

heart; while the venous system connects the posterior end of the tube, the inlet of the heart.

It is a simple linear pump.

Figure 1: A. Dorsal view of a late presomite embryo after removal of the amnion. B.Transverse section to show the position of the blood islands in the lateral splanchnic (vis-ceral) mesoderm layer. C. Cephalocaudal section showing the position of the pericardialcavity and cardiogenic field (Sadler 2006).

2 Segmentation and loop formation of the heart

The fused cardiac tube expands, some parts faster than others, resulting segmented tube with

dilatations separated by indentations (Figure 4). In anterior-posterior order, the dilatations

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Figure 2: Sequential stages in the cranial-caudal folding of the embryo (Sadler 2006).

are the truncus arteriosus, the bulbus cordis, the ventricle, the atrium, and the sinus venosus

(Figure 5, 6).

At first, the sinus venosus and the atrium are not enclosed within the pericardium cavity,

but because the cardiac tube outgrows the pericardial cavity, and because the tube is fixed

in the pericardium at both ends, the tube becomes U-shaped with the loop of U pointing

ventrally, i.e., the “bulboventricular loop”, which draws the atrium and the sinus venosus

into the pericardial cavity.

Figure 3: The sagittal (left), frontal (center) and transverse (right) views of the scanningelectron micrographs of the mouse embryo at gestation day 8. The cranial-caudal foldingof the embryo (left and center): the heart (green) folds under the pharynx (pink). Thelateral folding of the embryo (right): A: aortae (dorsal); G: gut tube; C: intraembryoniccavity (coelem); Sp: splanchnic (visceral) mesoderm; So: somatic (parietal) mesoderm.(http://www.med.unc.edu/embryo images/).

Continued cardiac growth results in the atrium occupying a position dorsal and slightly

rostral to the bulbus cordis and the ventricle and it expands toward the truncus arteriosus,

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which connects to the dorsal aortae through the aortic arches. At this time, the heart

becomes S-shaped, with the sinus venosus and the atrium as the first loop of S and the

ventricle and the bulbus cordis as the second loop of S.

Figure 4: Stages in the formation of the heart from the cardiac tube stage to the devel-opment of an U-shaped structure (McGeady etal 2006).

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Figure 5: Dorso-ventral and left lateral views of sequential stages in the segmentationand the S-shaped loop formation of the cardiac tube (McGeady etal 2006).

Figure 6: The frontal (on the left) and side (on the right) view of the scanning electronmicrographs of the mouse embryo at gestation day 9. The atrium (purple) is dorsal andslightly rostral to the ventricle (pink). (http://www.med.unc.edu/embryo images/).

3 Partitioning of the heart into four chambers

To circulate blood to the body and the lungs separately, the developing heart is partitioned

into four chambers (Figure 7, 10).

The septum intermedium grows from endocardial cushions to divide the atrioventricular

canal to left and right.

The interventricular septum grows near the interventricular sulcus to divide the ventricle

and the bulbus cordis into left and right ventricles. This division is not complete at first,

leaving interventricular opening (foramen). The interventricular foramen is later closed by

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the membranous interventricular septum, developed from the endocardial cushion, in such

a way that both ventricles open into the conus cordis, the remain of the bulbus cordis

connecting with truncus arteriosus.

Figure 7: Stages in the partitioning of the developing atrium and ventricle, leading tothe formation of left and right atria and ventricles. The arrow in F indicates the alloweddirection of blood flow through the foramen ovale (McGeady etal 2006).

The septum primum divides the common atrium into right and left atria. Initially the

foramen primum persists as an opening, but it eventually closes. Before it closes completely,

programmed cell death results in the foramen secundum. A second membrane—the septum

secundum arises from the dorsal right atrium and extends to the septum intermedium but

does not reach. The resulting opening is the foramen ovale. Because the foramen secundum

is stiffer than the foramen primum (also see Figure 8), when blood pressure is higher in the

right atrium, the blood flows into the left atrium, but not the other way around.

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4 Division of the heart inlet

The two horns of the sinus vernosus, i.e., the inlets from the right and left veins, have very

different ends in the development. The left horn eventually develops into the coronary sinus.

The right horn is favoured and incorporated into the right atrium, and also forms part of

the cranial and caudal vena cava (Figure 8).

The pulmonary veins are incorporated into the left atrium.

Figure 8: Incorporation of the right sinus horn and the pulmonary veins into the atriumat two stages of development (A, B). 1: Opening of right sinus horn into the atrium; 2:Opening of the pulmonary veins into the atrium; 3: Septum primum; 4: Foramen pri-mum; 5: Incorporated portion of right sinus horn; 6: Incorporated portion of pulmonaryveins; 7: Right atrium; 8: Left atrium; 9: Opening to caudal vena cava; 10: Opening tocranial vena cava; 11: Septum secundum; 12: Foramen secundum; 13: Foramen ovale.Modified from Hyttel etal 2010.

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5 Division of the heart outlet

The conus cordis and the truncus arteriosus are divided by growing pair of cushions from

their walls to form aorticopulmonary septum. The outlet rotates 180 degrees, such that the

aortic trunk on the right at the top is linked down to the left ventricle and the pulmonary

trunk on the left at the top is link down to the right ventricle (Figure 9, 10).

Figure 9: Partitioning of the concus cordis and truncus arteriosus into the aortic and pul-monary truncks respectively, A and B. The spiral arrangement and the final relationshipis also shown in C (McGeady etal 2006).

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Figure 10: The scanning electron micrographs of the mouse embryo: left, the frontalsection of the heart (gestation day 10) shows that blood from the atrium (purple) passesto the ventricle (pink) by the atrioventricular canal (red arrow) and the beginnings ofinteratrial septum formation can be seen (A); right, the transverse section of the truncusarteriosus (gestation day 12) shows that cushions (green) formed within the truncusarteriosus will fuse to form the aortico-pulmonary septum separating the aortic (red)and pulmonary (blue) flows. (http://www.med.unc.edu/embryo images/).

6 Formation of blood cells

The formation of blood cells, haematopoiesis, occurs in three overlapping periods (Figure 11):

Figure 11: Three periods of blood cell formation.

The definitive haematopoietic stem cells are thought to be formed intra-embryonically,

in the viseral lateral plate mesoderm closer to the aorta, in the aorta-gonad-mesonephric

(AGM) region. Pluripotent haematopoietic stem cells also appear to be generated along

with the endothelium of the placental blood vessels. Those two source of blood stem cells,

with a potential third contribution from the haemangioblasts in the yolk sac mesoderm,

colonize the fetal liver and the bone marrow for blood formation.

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7 Developing vascular system

The embryonic blood supply is accomplished by three circulation loops (Figure 12):

Figure 12: The rudimentary cardiavascular system of an embryo showing three circula-tion arcs (http://www.eevec.vet.ed.ac.uk/).

At the beginning of development, both the arterial and venous systems have symmetric

left and right branches. However, the symmetry is broken during further development—at

the same time that the outlet and the inlet of the heart break the symmetry shown in the

previous sections.

With the formation of six branchial arches, six corresponding arterial arches (aortic

arches) form between the dorsal and ventral aortae on each side. However, only the third,

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fourth, and sixth aortic arches form prominent components of the developing circulatory

system (Figure 13).

The left and right third aortic arches form the left and right common carotid arteries. The

right fourth aortic arch forms the proximal right subclavian artery, while the left is retained

as the aortic arch connecting the left ventricle to the left dorsal aorta. The proximal left and

right sixth aortic arches become the proximal left and right pulmonary arteries, while the

distal right atrophies and the distal left forms the ductus arteriosus—the important shunt

for the embryo to link the pulmonary artery with the dorsal aorta.

Figure 13: Ventral aspect of the development of the aortic arches. A: Initial stage ofdevelopment. B: Progressed stage of development C: Final stage of development. Thearrow in A indicates where the truncus arteriosus is attached to the ventral aortae. I-VI:Aortic arches 1-6; 1: Right dorsal aorta; 2: Right ventral aorta; 3: Aorta; 4: Truncusbrachiocephalicus; 5: Left subclavian artery; 5’: Right subclavian artery; 6: Left commoncarotid artery; 7: Left external carotid artery; 8: Left internal carotid artery; 9: Ductusarteriosus; 10: Left pulmonary artery; 10’: Right pulmonary artery; 11: N. Vagus; 12:N. laryngeus recurrens. Modified from Hyttel etal 2010.

The dorsal aortae atrophy between the third and fourth aortic arches. The left and

right cranial parts of dorsal aortae give rise to the left and right internal carotid arteries.

The caudal parts of dorsal aortae are mostly fused to a single caudal aorta and give rise

to dorsal, lateral and ventral segmental arteries. In particular, a pair of dorsal segmental

arteries, together with parts of the dorsal aortae form the left subclavian artery and the

rest of the right subclavian artery. Pairs of lateral arteries develop into ovarian, testicular,

adrenal, and renal arteries. The ventral segmental arteries are associated with the yolk sac

(the most cranial, vitelline arteries, becoming the coeliac artery and the cranial mesenteric

artery) and the allantois (the most caudal, allantoic arteries, becoming the internal iliac

arteries and the cranial vesical arteries).

The most prominent symmetry breaking of the venous system is associated with anasto-

moses of the vitelline and allantoic (umbilical) veins in the liver. During the development,

the left vitelline vein and the right allantoic vein involute and disappear. The proximal left

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allantoic vein forms anastomosis with the proximal portion of the right vitelline vein and

persists as the ductus venosus which shunts oxygenated blood from the placenta through

the liver. The proximal right vitelline vein develops into the hepatocardiac portion of the

caudal vena cava, connecting the ductus venosus and the heart. The distal portion of the

right vitelline vein develops into the portal vein (Figure 14).

Figure 14: Outline of foetal circulation in utero (McGeady etal 2006).

8 Changes in circulation at birth

At birth, the blood flow from the placenta to the fetus is stopped by the contraction of the

ductus venosus and the left allantoic vein. The blood flow to the placenta is stopped by

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contraction of the allantoic arteries (figure 15).

Without oxygenation of the blood from the placenta, respiration starts. This stimulates

the pulmonary blood circulation. As a result, the blood pressure in the left atrium in-

creases, which closes the foramen ovale. The ductus arteriosus closes reflexively, preventing

deoxygenated blood in the pulmonary trunk from entering the aorta.

Figure 15: Changtes in circulation post-natal (McGeady etal 2006).

9 Reference

Hyttel S, Sinowatz F, Vejlsted M (2010) Essentials of domestic animal embryology.

McGeady TA, Quinn PJ, Fitzpatrick ES, Ryan MT (2006) Veterinary embryology.

Sadler TW (2006) Langman’s medical embryology.

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10 Quiz

1) Cardiac precursor cells form from which layer?

a) Mesoderm

b) Ectoderm

c) Endoderm

2) What structure does the proximal part of the bulbus cordis become?

a) Right Ventricle

b) Left Ventricle

c) Aortic & Pulmonary trunks

d) Aorta & Pulmonary Artery

e) Left & Right Atria

3) What structure does the distal part of the bulbus cordis become?

a) Right Ventricle

b) Left Ventricle


d) Left & Right Atria

4) What structure does the truncus arteriosus become?

a) Right Ventricle

b) Left Ventricle


d) Left & Right Atria

5) What major structure is formed in part by the sinus venosus?

a) Aorta

b) Left Ventricle

c) Right Ventricle

d) Left Atrium

e) Right Atrium

6) Where is the foramen (ostium) primum formed?

a) Between Right and Left Ventricles

b) Between Right and Left Atria

c) Between Right Atrium and Ventricle

d) Between Left Atrium and Ventricle

e) Within the Coronary Sinus

7) All arteries, veins, and lymphatic channels form from ____.

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a) Ectoderm

b) Mesoderm

c) Endoderm

d) Chorion

e) Villi

8) Which nerve is associated with the aortic arches VI?

a) V --- Trigeminal Nerve

b) VI --- Abducent Nerve

c) IX --- Glossopharyngeal Nerve

d) X --- Vagus Nerve

e) XI --- Accessory Nerve

9) Aortic arch IV forms the ____ on the right side of the embryo and

the ____ on the left.

a) Right subclavian artery; Arch of aorta

b) Ductus arteriosus; Pulmonary Artery

c) Arch of aorta; Pulmonary Artery

d) Ductus arteriosus; Right subclavian artery

e) Arch of aorta; Ductus arteriosus

10) What organ do the vitelline arteries supply?

a) body

b) liver

c) placenta

d) mesonephro

e) york sac

11) At birth, a child’s skin appears much less pink than would be expected.

The physician determines that the child’s ductus arteriosus did not close.

The child has a blue tint because the ductus arteriosus is shunting blood

from the ____ to the ____.

a) Right Atrium; Left Atrium

b) Pulmonary Artery; Aorta

c) Right Ventricle; Left Ventricle

d) Inferior Vena Cava; Right Atrium

e) Descending Aorta; Umbilical Arteries

12) In utero, the ductus venosus helps shunt blood away from the very first

organ it reaches to more important organs like the brain. This shunt

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bypasses the ____.

a) Lungs

b) Aorta

c) Spleen

d) Pancreas

e) Liver

13) Name the structures 3, 4, 11, and 12 in the following figure of the

ventral view of the developing atrium in two stages A and B.

Answer:

1-a 2-a 3-c 4-c 5-e 6-b 7-b 8-d 9-a 10-e 11-b 12-e

13: septum primum, foramen primum, septum secundum, and foramen secundum.

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Cardiovascular Development - University of Pennsylvaniadove.med.upenn.edu/~dawei/DB2013/blood-heart-vascular-handout-2… · 2. outline the fusion of the cardiac tube to form the