Development of

Circulatory System
Descriptive terms of position,
direction, and planes of the body.
A - Lateral view of an adult in the
anatomical position.
B - Lateral view of a 5-week embryo.
C and D - Ventral views of a 6-week embryo; E - Lateral view of a 7-week embryo.
Gametogenesis

Fertilization

Preimplantation

Implantation

Embryonic disk

Embryonic phase

Fetal phase
 Scanning electron micrographs of A
uncompacted and B compacted eight-cell
mouse embryos. In the uncompacted state,
outlines of each blastomere are distinct,
whereas after compaction, cell–cell contacts
are maximized, and cellular outlines are
indistinct.

Section of a 107-cell human blastocyst showing

inner cell mass and trophoblast cells.
 B. Schematic representation of a human blastocyst recovered from the uterine
cavity at approximately 4.5 days.
C. Schematic representation of a blastocyst at the sixth day of development
showing trophoblast cells at the embryonic pole of the blastocyst penetrating the
uterine mucosa.
The human blastocyst begins to penetrate the uterine mucosa by the sixth day of
development.
The wall of the uterus consists of three layers:

1. Endometrium or mucosa lining the inside wall

2. Myometrium, a thick layer of smooth muscle
3. Perimetrium, the peritoneal covering lining the outside wall.
 A 7.5-day human blastocyst, partially embedded in the endometrial stroma. The
trophoblast consists of an inner layer with mononuclear cells, the cytotrophoblast,
and an outer layer without distinct cell boundaries, the syncytiotrophoblast.
The embryoblast is formed by the epiblast and hypoblast layers. The amniotic cavity
appears as a small cleft.
 Section of a 7.5-day human blastocyst (×100).
Note the multinucleated appearance of the
syncytiotrophoblast, large cells of the
cytotrophoblast, and slit-like amniotic cavity.

Fully implanted 12-day human blastocyst (×100).

Note maternal blood cells in the lacunae, the
exocoelomic membrane lining the primitive
yolk sac, and the hypoblast and epiblast.
9-day human blastocyst. The syncytiotrophoblast shows a large number of lacunae.
Flat cells form the exocoelomic membrane. The bilaminar disc consists of a layer
of columnar epiblast cells and a layer of cuboidal hypoblast cells. The original
surface defect is closed by a fibrin coagulum.
 Human blastocyst of approximately 12 days. The trophoblastic lacunae at the
embryonic pole are in open connection with maternal sinusoids in the
endometrial stroma. Extraembryonic mesoderm proliferates and fills the
space between the exocoelomic membrane and the inner aspect of the
trophoblast.
A 13-day human blastocyst. Trophoblastic lacunae are present at the embryonic as
well as the abembryonic pole, and the uteroplacental circulation has begun. Note the
primary villi and the extraembryonic coelom or chorionic cavity. The secondary yolk
sac is entirely lined with endoderm.
The second week of development is known as the week of 2’s:

1. The trophoblast differentiates into 2 layers:

the cytotrophoblast and syncytiotrophoblast

2. The embryoblast forms 2 layers: the epiblast and hypoblast

3. The extraembryonic mesoderm splits into 2 layers:

the somatic and splanchnic layers

4. Two cavities form: the amniotic and yolk sac cavities

The most characteristic event occurring during the third week of gestation is
gastrulation, the process that establishes all three germ layers (ectoderm,
mesoderm, and endoderm) in the embryo. Gastrulation begins with formation of
the primitive streak on the surface of the epiblast.

Implantation site at the end of the second week

Representative view of the germ disc at

the end of the second week of development.
The hypoblast and epiblast are in contact with
each other, and the primitive streak forms
a shallow groove in the caudal region
of the embryo.
Cells of the epiblast migrate toward the primitive streak. Upon arrival in the
region of the streak, they become flask-shaped, detach from the epiblast,
and slip beneath it. This inward movement is known as invagination. Cell
migration and specification are controlled by fibroblast growth factor 8 (FGF8),
which is synthesized by streak cells themselves.
Dorsal side of the germ disc from a 16-day embryo
indicating the movement of surface epiblast cells
(solid black lines) through the primitive streak and
node and the subsequent migration of cells between
the hypoblast and epiblast (broken lines).

Cross section through the cranial

region of the streak at 15 days
showing invagination of epiblast cells.
The first cells to move inward
displace the hypoblast to create
the definitive endoderm. Once
definitive endoderm is established,
inwardly moving epiblast forms
mesoderm.
Once the cells have invaginated, some displace the hypoblast, creating the
embryonic endoderm, and others come to lie between the epiblast and newly
created endoderm to form mesoderm. Cells remaining in the epiblast then form
ectoderm. Thus, the epiblast, through the process of gastrulation, is the source of
all of the germ layers, and cells in these layers will give rise to all of the tissues
and organs in the embryo.

Dorsal view of the germ disc showing the primitive

streak and a fate map for epiblast cells. Specific regions
of the epiblast migrate through different parts of the node
and streak to form mesoderm. Thus, cells migrating at the
cranialmost part of the node will form the notochord (n);
those migrating more posteriorly through the node and
cranialmost aspect of the streak will form paraxial
mesoderm (pm; somitomeres and somites); those
migrating through the next portion of the streak will form
intermediate mesoderm (im; urogenital system); those
migrating through the more caudal part of the streak will
form lateral plate mesoderm (lpm; body wall); and those
migrating through the most caudal part will contribute
to extraembryonic mesoderm (eem; chorion).
 A. Cross section through a 21-day embryo in the region of the mesonephros showing
parietal and visceral mesoderm layers. The intraembryonic cavities communicate with
the extraembryonic cavity (chorionic cavity).

B. Section at the end of the fourth week. Parietal mesoderm and overlying ectoderm
form the ventral and lateral body wall. Note the peritoneal (serous) membrane.
The ectodermal germ layer gives rise to the organs and structures that
maintain contact with the outside world:
● Central nervous system;
● Peripheral nervous system;
● Sensory epithelium of ear, nose, and eye;
● Skin, including hair and nails; and
● Pituitary, mammary, and sweat glands and enamel of the teeth.

The endodermal germ layer provides the epithelial lining of the gastrointestinal
tract, respiratory tract, and urinary bladder. It also forms the parenchyma of
the thyroid, parathyroids, liver, and pancreas. Finally, the epithelial lining of
the tympanic cavity and auditory tube originates in the endodermal germ layer.
Important components of the mesodermal germ layer are paraxial,
intermediate, and lateral plate mesoderm. Paraxial mesoderm forms
somitomeres, which give rise to mesenchyme of the head and organize into somites
in occipital and caudal segments. Somites give rise to the myotome (muscle
tissue), sclerotome (cartilage and bone), and dermatome (dermis of the skin),
which are all supporting tissues of the body.

Mesoderm also gives rise to the vascular system (i.e., the heart, arteries, veins,
lymph vessels, and all blood and lymph cells).
Furthermore, it gives rise to the urogenital system: kidneys, gonads, and their
ducts (but not the bladder). Finally, the spleen and cortex of the suprarenal glands
are mesodermal derivatives.
A. Lateral view of a 14-somite embryo (approximately 25 days). Note the bulging
pericardial area and the first and second pharyngeal arches.
B. The left side of a 25-somite embryo approximately 28 days old. The first three
pharyngeal arches and lens and otic placodes are visible.
Pharyngeal arches are rod-like thickenings of mesoderm present in the wall
of the foregut.
• At first there are six arches. The fifth arch disappears and only five remain.
• The ventral ends of the arches of the right and left sides meet in the
middle line in the floor of the pharynx.
• In the interval between any two arches, the endoderm (lining the pharynx) is
pushed outwards to form a series of pouches. These are called endodermal,
or pharyngeal pouches.
Fertilization of the ovum takes place in the ampulla of the uterine tube.
The fertilized ovum is a large cell. It undergoes a series of divisions
(clevage).

Path taken by the sperm (pink),

and ovum (blue), for fertilization.

Some stages in segmentation of the fertilized

ovum; (A) Two-cell stage; (B) Three-cell stage;
(C) Four-cell stage; (D) Morula.
 When there are 16 cells, the ovum is called a morula. It has an inner
cell mass covered by an outer layer of cells, the trophoblast.

Formation of blastocyst.

Fluid partially separates the inner cell mass from trophoblast.

The morula now becomes a blastocyst.
 Differentiation of endoderm and ectoderm, and
the formation of the amniotic cavity and the yolk sac.

The cells of the inner cell mass multiply,

and are rearranged to form an embryonic
disc having two germ layers. These layers
are the ectoderm and endoderm. Later, a
third germ layer, the mesoderm, forms
between ectoderm and endoderm.
A cavity appears on the ectodermal side
of the disc. This is the amniotic cavity.
Another cavity appears on the
endodermal side. This is the yolk sac.

At first the walls of the amniotic cavity and yolk sac are in contact with
trophoblast.
They are soon separated from the latter by extra-embryonic mesoderm.
 Formation of extra-embryonic mesoderm and extra-embryonic coelom.
Note carefully, the composition of the amnion, and of the chorion.

A cavity, the extra-embryonic coelom appears and splits the extra-embryonic

mesoderm into a somatopleuric layer (in contact with trophoblast) and a
splanchnopleuric layer (in contact with yolk sac).

The trophoblast and underlying somatopleuric mesoderm form a membrane

called the chorion.
The cells forming the wall of the amniotic cavity form the amnion.
The amniotic cavity is now attached to trophoblast by some mesoderm into which
the extra-embryonic coelom has not extended. This mesoderm forms the
connecting stalk.
If we view the embryonic disc from the ectodermal side we see that near one
edge it has a rounded area called the prochordal plate. Here ectoderm and
endoderm are not separated by mesoderm.

Embryonic disc after establishment of a

central axis. (B) represents a section
along the central axis.
An elevation, the primitive streak, is also seen on the embryonic disc.
A line drawn through the prochordal plate and the primitive streak
divides the embryonic disc into right and left halves.

Appearance of primitive streak. Formation of intra-embryonic mesoderm.

(B) is a section along axis XY shown in (A). (B) is a section along axis KL in (A).
Cells multiplying in the primitive streak move into the interval
between ectoderm and endoderm and form the mesoderm (third
germ layer).
Caudal to the primitive disc we see a round area called the cloacal
membrane. It is made up only of ectoderm and endoderm.

Spread of intra-embryonic mesoderm. Note that the mesoderm comes to lie

between ectoderm and endoderm in all parts of the embryonic disc except
at
(1) the prochordal plate, (2) the cloacal membrane, and (3) the region of the
notochord.
Dorsal view of a late presomite embryo (approximately 18 days) after removal of the
amnion. Progenitor heart cells have migrated and formed the horseshoe-shaped
primary heart field (PHF) located in the splanchnic layer of lateral plate mesoderm. As
they migrated, PHF cells were specified to form left and right sides of the heart and to
form the atria, left ventricle, and part of the right ventricle. The remainder of the right
ventricle and the outflow tract consisting of conus cordis and truncus arteriosus are
formed by the secondary heart field (SHF). B. Transverse section through a
similar-staged embryo to show the position of PHF cells in the splanchnic mesoderm
layer.
C. Cephalocaudal section through a similar-staged embryo showing the position of the
pericardial cavity and PHF.
Drawing showing the SHF that lies in
splanchnic mesoderm at the posterior of the
pharynx. The SHF provides cells that lengthen
the out-flow region of the heart, which
includes part of the right ventricle and the
outflow tract (conus cordis and truncus
arteriosus). Neural crest cells, migrating from
cranial neural folds to the heart through
pharyngeal arches in this region, regulate the
SHF by controlling FGF concentrations.
Disruption of the SHF causes shortening of the
outflow tract region, resulting in outflow tract
defects.
Effects of the rapid growth of the brain on positioning of the heart. Initially,
the cardiogenic area and the pericardial cavity are in front of the
oropharyngeal membrane. A. 18 days. B. 20 days. C. 21 days. D. 22 days.
Transverse sections through embryos at different stages of development,
showing formation of a single heart tube from paired primordia. A. Early
presomite embryo (17 days). B. Late presomite embryo (18 days). C. Eight-somite
stage (22 days). Fusion occurs only in the caudal region of the horseshoe-shaped
tube. The outflow tract and most of the ventricular region form by expansion and
growth of the crescent portion of the horseshoe.
 Frontal view of an embryo showing the
heart in the pericardial cavity and the
developing gut tube with the anterior and
posterior intestinal portals.
The original paired tubes of the heart
primordial have fused into a single tube
except at their caudal ends, which remain
separate. These caudal ends of the heart tube
are embedded in the septum transversum,
while the outflow tract leads to the aortic sac
and aortic arches.
 Cephalic end of an early somite embryo. The developing endocardial heart
tube and its investing layer bulge into the pericardial cavity. The dorsal
mesocardium is breaking down.
Formation of the cardiac loop. A. 22 days. B. 23 days. C. 24 days. D. Frontal view
of the heart tube undergoing looping in the pericardial cavity. The primitive
ventricle is moving ventrally and to the right, while the atrial region is moving
dorsally and to the left (arrows).
Formation of the septum in the atrioventricular canal. From left to right,
days 23, 26, 31, and 35. The initial circular opening widens transversely.
 Formation of the atrioventricular valves and chordae tendineae. The
valves are hollowed out from the ventricular side but remain attached
to the ventricular wall by the chordae tendineae.
 The cardiogenic plate is formed by a
collection of mesoderm cells in the
most anterior part of the embryo.

Through the rotation following the

cranial folding of the embryo the
pericardial cavity comes to lie ventrally
from the cardiac anlage and, as things
progress, will surround it.

The outer layer of the heart is formed by the epicardium that originally arises from the
extracardial anlage, the proepicardial serosa cells. These grow over the myocardium and issue
from a collection of cells in the septum transversum that lie ventrally to the liver bud near the
sinus venosus.
Presumably, the subepicardial mesenchymal cells also come from the epicardial layer. Besides the
epicardial layer, it appears that the proepicardial serosal cells also form the endothelium and the
smooth muscle cells of the coronary arteries. Moreover they play a modulating role in the
development of the myocardium.
The early processes of cardiac formation, in
particular the forming of the loop, are very
interesting from many points of view. A long, closed
tube arises out of the endocardial plexus.
This tubular heart largely represents the anlage for
the trabeculated part of the future right and left
ventricles .
 In the early part of stage 9 the embryo
is shaped like a foot sole and consists
of ectoderm, mesoderm and endoderm
cell layers. In the extraembryonic region
the lateral plate mesoderm becomes
split. The visceral layer, covering the
umbilical vesicle, forms the splanchnopleura
together with the adjacent endoderm.
The parietal layer covers the amniotic cavity
and together with the adjacent ectoderm
is named somatopleura. In the lateral
plate mesoderm itself, probably as a result
of uneven growth, dehiscences (splits open),
thereby creating small, fluid-filled cleavages.
These spaces fuse in the area of the head and form the pericardial cavity that corresponds to the
cranial part of the U-shaped intraembryonic coelom. During the course of stages 9 and 10 the
formation of the head fold occurs via the cranial flexion. Thereby, the future outflow
tract (arterial pole), which at the start of the cardiac formation 9 lies caudally to the inflow
tract (venous pole), comes to lie cranially due to this cranial flexion of the embryo through a 180
degree rotation and the relative shrinking of the umbilical vesicle.
The pericardial cavity expands on both sides of
the cardiac anlage and invaginates the
myocardiac mantle with the cardiac loop. This
results in the mesocardium being transiently
formed on the dorsal side of the cardiac loop.
In the beginning of the early embryonic
stages (stages 8, ca. the 23rd day 8), the
heart forms outside the embryonic disk.
It is only with the flexion of the embryo
that the heart comes to lie within and
ventral to the embryo.
Through the growth of the brain the embryo
bends forward progressively and in stage
14. It attains its maximum flexion.
However, the heart continues to descend
further and, at the end of the embryonic
period, comes to lie in the thoracic region.
With ca. the 28th day the heart of the embryo
begins to beat. Initially this only causes a back
and forth movement of the blood to occur, but
very soon a directional flow of the blood
begins from the inflow tract over the atrium
and ventricle part in the conus cordis and the
pair of aortic arches. The inflow tract contains
oxygen-rich blood from the umbilical veins and
a contribution from the omphalomesenteric
veins.
With the formation of the cardiac loop the inflow tract
migrates with the sinus venosus and the two sinus horns up
and to the rear.
In addition, the vein opening that is originally located
symmetrically is also shifted towards the right, together
with its various branches.
In the beginning, the sinus venosus contains only blood
from the two umbilical veins (oxygen- and nutrient-rich
from the placenta), the omphalomesenteric veins and finally
the common cardinal veins, which receive the blood from
the embryonic somatic circulation proper.
In summary it can be said that for the transformation from a
serial to a parallel flow both outer as well as inner
transformation processes are responsible. At the atrium level
these are:
The relocation of the sinus venosus to the right
The relocation of the av level into the middle
The septation of the common atrium
The septum formation at the av level
Very early in cardiac development the atria,
which have formed in the rear upper part, are
separated from the ventricles by the sulcus
atrio-ventricularis.
In the interior of the heart, endocardial cushions
form that grow first both dorsally and ventrally
into the lumen.
Somewhat later, these two cushions fuse in the
middle of the lumen and thereby divide the av-
canal into right and left openings.
The first morphologically visible differentiation of the
conduction system in human embryos is the
sinu-atrial node. It is located in the wall of the right
sinus horn near its opening in the right atrium, i.e., in
the sulcus terminalis.
The atrioventricular conduction system, the av-node
or Aschoff-Tawara's node, becomes discernible
somewhat later. It lies at the dorsal circumference of
the av-canal in the inner layer of the myocardium at
the beginning of the dorsal av-septum.
From it derives the His' bundle, which extends over
the dorsal av-septum and forms the connection
between the atrial and ventricular myocardium Here
it divides into three subendocardial bundle branches.
They extend into the cardiac apex region where a
separation into fine Purkinje's fibers occurs. In situ,
this conduction system forms itself from specialized
myocardial cells. Once the sinu-atrial node as well as
the av-node and His' bundle have been
differentiated, the cardiac frequency increases
rapidly and reaches 140 beats/min. The region with
the highest frequency (sinus region) takes over the
pacemaker function.
The first development of the heart takes place
independently of its innervation. Later, though,
three differing sources for cardiac innervation can
be found.
The parasympathetic innervation (cholinergic
system) arises from cardiac components of the
cranial neural crest cells. The neurons of the
cardiac ganglia, which represent parasympathetic
neurons of the second order, migrate directly from
the neural crest into the heart. Somewhat later,
the axons of the first order nerves obtain access to
the heart via the vagus nerve.
The parasympathetic innervation slows the
heartbeat.
The sympathetic nerve fibers
(adrenergic system), which speed up the
heartbeat as well as promote the positive
inotropism of the cardiac musculature, arise
from the thoracic sympathetic ganglia that in
their turn come originally from the thoracic
neural crest cells.
The third component of the innervation comes
directly from the vagus nerve. These are sensory
nerves that arise from the ectodermal placode
of the nodose ganglion.
The first signs of vessel formation are found in the region of the
umbilical vesicle (extraembryonic) at stage 8. Mesodermal cell masses
are seen there that are also known as hemangioblasts. Within these
mesodermal cell masses, those in the center become rounded and
develop into the precursors of the blood cells (hemocytoblasts) while
the peripheral cells come together as delimiting endothelial cells
(angioblasts). Both the formation of the vessels as well as that of the
cardiac tube have thus a close relationship to the endoderm that
appears to have an inductive influence. Already before stage 9.
Intraembryonic vessels also form from angioblasts that have
differentiated within the splanchnopleurae. Angioblast cells migrate
away and settle in the various organs, attracted by angiogenetic
factors that stimulate vessel formation.
In both the venous and the lymphatic sections the embryonic veins form the basis
for vessel formation.
In an initial differentiation step in the young embryo a portion of the endothelial
cells in certain regions of the cardinal vein system begins to produce special
receptor molecules (Prox-1). This is the first step in the direction of lymphatic
vessel determination. Now follow further expressions of receptor patterns that
are characteristic for either blood or lymphatic vessels and which are preserved
even into adulthood.
Normal Heart Isolated defect in the membranous postion of the
interventricular septum. Blood from the left
ventricle flows to the right through the
interventricular foramen
(A) Persistence of the distal portion of the right dorsal aorta.
(B) The double aortic arch forms a vascular ring around the trachea and esophagus.