Vasculogenesis: formation

of blood vessels from blood

islands

Lateral Plate
Mesoderm

 William Harvey viewed the heart as the undisputed ruler of the

body
through whose divinely ordained powers the lawful growth of the
organism was assured

Some embryologists looked at the heart as more of a servant

than a ruler
the chamberlain of the household who assured that the nutrients
reached the centrally located brain and peripherally located muscles

 On either side of the intermediate mesoderm resides the lateral plate

mesoderm
Each plate splits horizontally into:
the dorsal somatic (parietal) mesoderm, which underlies the ectoderm,
the ventral splanchnic (visceral) mesoderm, which overlies the endoderm

During later development, the right- and left-side coeloms fuse, and
folds of tissue extend from the somatic mesoderm, dividing the
coelom into separate cavities.
Coelom is the space between these layers becomes the body cavity

In mammals
Coelom is subdivided into:
1. pleural
2. pericardial
3. peritoneal
The mechanism for creating the linings
of these body cavities from the lateral
plate mesoderm has changed little
throughout vertebrate evolution

In 3-day chick embryos and 5-week

human embryos, the heart is a twochambered tube, with one atrium
and one ventricle
In the chick embryo, the unaided eye
can see the remarkable cycle of
blood entering the lower chamber
and being pumped out through the
aorta.
The looping of the heart converts the
original anterior-posterior polarity of
the heart tube into the right-left
polarity seen in the adult
Specification of the atrium and ventricles
occurs even before heart looping.

 The looping of the heart converts the original anterior-posterior

polarity of the heart tube into the right-left polarity seen in the
adult
Thus, the portion of the heart tube destined to become the right
ventricle lies anterior to the portion that will become the left
ventricle.
Within the heart primordium
Nkx25 regulates the Hand1 and Hand2 transcription factors
Hand1 becomes restricted to the future left ventricle
Hand2 to the right, as looping commences

Without these proteins, looping fails to occur normally and the

ventricles fail to form properly

Cascade of heart development

 The Pitx-2 transcription factor,

activated solely in the left side of
the lateral plate mesoderm critical
for proper heart looping
regulate the expression of proteins
such as the extracellular matrix
protein flectin to regulate the
physical tension of the heart tissues
on the different sides
Transcription factors Nkx2-5 and
MEF2C also activate theXingene,
whose protein product, Xin (Chinese for
heart), may mediate the cytoskeletal
changes essential for heart looping

 The separation of atrium from ventricle is specified by

the several transcription factors that become restricted
to either the anterior or the posterior portion of the
heart tube
. The partitioning of this tube into a distinctive atrium
and ventricle is accomplished when cells from the
myocardium produce a factor (probably transforming
growth factor 3) that causes cells from the adjacent
endocardium to detach and enter the hyaluronate-rich
cardiac jelly between the two layers

In humans, these cells cause the formation of an endocardial

cushion that divides the tube into right and left atrioventricular
channels

Formation of the chambers of the heart

 The primitive atrium is partitioned by twoseptathat grow

ventrally toward the endocardial cushion.
The septa, have holes in them, so blood can still cross from
one side into the other.
Crossing of blood is needed for the survival of the fetus
before circulation to functional lungs has been established.
With the formation of the septa (which usually occurs in the
seventh week of human development), the heart is a fourchambered structure with the pulmonary artery connected to
the right ventricle and the aorta connected to the left.

The Heart

The Heart
The circulatory system is one of the
great achievements of the lateral plate
mesoderm
Consisting of a heart, blood cells, and
an intricate system of blood vessels
Provides nourishment to the developing
vertebrate embryo
Circulatory system first functional
unit; Heart first functional organ
Arises from two regions of splanchnic
mesoderm

Specification of heart tissue and fusion of

heart rudiments
In amniote vertebrates, the embryo is a flattened disc and the
lateral plate mesoderm does not completely encircle the yolk
sac
The presumptive heart cells originate in the early primitive
streak, posterior to Hensen's node and extending about
halfway down its length
These cells migrate through the streak and form two groups of
mesodermal cells lateral to Hensen's node
These groups of cells are called the cardiogenic mesoderm
The cells forming the atrial and ventricular musculature, the
cushion cells of the valves, the Purkinje conducting fibers, and

Figure 15.2; Heart-forming cells of the chick embryo.

Specification of heart tissue and fusion of

heart rudiments
When the chick embryo is only 18 20 hours old, the
presumptive heart cells move anteriorly between the
ectoderm and endoderm toward the middle of the
embryo, remaining in close contact with the endodermal
surface
When these cells reach the lateral walls of the anterior
gut tube, migration ceases.
The directionality provided by the foregut endoderm
If the cardiac region endoderm is rotated, migration of the
cardiogenic mesoderm cells is reversed.

Specification of heart tissue and fusion of

heart rudiments
The endoderm and primitive streak specify the some of the
cardiogenic cells to become heart muscles
Cerberus and an unknown factor, possibly BMP2 in the anterior
endoderm, induce the synthesis of the Nkx2-5 transcription factor
in the migrating mesodermal cells
Nkx2-5 is a critical protein in instructing the mesoderm to
become heart tissue, and it activates the synthesis of other
transcription factors (especially members of the GATA and MEF2
families).
Working together, these transcription factors activate the
expression of genes encoding cardiac muscle-specific proteins
(such as cardiac actin, atrial naturetic factor, and the alpha

Specification of heart tissue and fusion of

heart rudiments
Specification of the heart cells occurs gradually, with the
ventricular cells becoming specified prior to the atrial cells
Cell differentiation occurs independently in the two heartforming primordia that are migrating toward each other
As they migrate, the cells begin to express N-cadherin on their
apices and join into an epithelium.
A small population of these cells then downregulates N-cadherin
and delaminates from the epithelium to form the endocardium.
The epithelial cells form the myocardium
The myocardium will form the heart muscles

The endocardium forms the inner lining

of the heart, the myocardium forms the
heart muscles, and the epicardium will
eventually cover the heart. Transverse
sections through the heart-forming region
of the chick embryo are shown at
(A) 25 hours

(B) 26 hours

Figure 15.3 Formation of the chick heart from the splanchnic lateral plate mesoderm.

(C) 28 hours

(D) 29 hours.

Figure 15.3 Formation of the chick heart from the splanchnic lateral plate mesoderm.

Specification of heart tissue and fusion of

heart rudiments
As neurulation proceeds, the foregut is formed by the inward
folding of the splanchnic mesoderm
This movement brings the two cardiac tubes together,
eventually uniting the myocardium into a single tube.
The bilateral origin of the heart can be demonstrated by
surgically preventing the merger of the lateral plate mesoderm
This results in a condition calledcardia bifida, in which a separate
heart forms on each side of the body

The two endocardia lie within this common tube for a short
while, but these will also fuse.

(A)Stage 9 chick neurula

(B)Cross section of the
same stage neurula
(C)Stage 10 chick embryo
(D)Cross section through a
similar stage 10 chick
embryo
(E)Cardia bifida in chick
embryo, caused by
surgically cutting the
ventral midline, thereby
preventing the two heart
primordia from fusing

Figure 15.4 Fusion of the right and left heart rudiments to form a single
cardiac tube.
The cells fated to form the heart myocardium are shown by staining for
the Xinmessage, whose protein product will be essential for the looping of the
heart tube.

Specification of heart tissue and fusion of

heart rudiments
This fusion occurs at about 29 hours in chick
development and at 3 weeks in human gestation
The unfused posterior portions of the endocardium
become the openings of thevitelline veinsinto the
heart.
These veins will carry nutrients from the yolk sac into
thesinus venosus.
The blood then passes through a valvelike flap into the
atrial region of the heart. Contractions of thetruncus
arteriosusspeed the blood into the aorta.

Specification of heart tissue and fusion of

heart rudiments
Pulsations of the heart begin while the paired primordia are still
fusing.
The pacemaker of this contraction is the sinus venosus.
Contractions begin and a wave of muscle contraction is propagated
up the tubular heart.

In this way, the heart can pump blood even before its intricate
system of valves has been completed.
Heart muscle cells have their own inherent ability to contract
In the embryo, these contractions become regulated by
electrical stimuli from the medulla oblongata via the vagus
nerve, and by 4 days, the electrocardiogram of a chick embryo

Formation of Blood
Vessels

Blood Vessels
Although the heart is the first functional
organ of the body, it does not even
begin to pump until the vascular system
of the embryo has established its first
circulatory loops.
The blood vessels form independently,
linking up to the heart soon rather than
sprouting from the heart, afterward.
Chance plays a major role in establishing
the microanatomy of the circulatory
system.
Development of the circulatory system is
severely constrained by physiological,
physical, and evolutionary parameters
The construction of any circulation system must negotiate among all of these physical, physiological, and
evolutionary constraints

Constraints on how blood vessels may be

constructed
physiological

new organisms have to function even as they develop

evolutionary
even though our physiology does not require such a structure, our embryonic
condition

Vasculogenesis: formation
of blood vessels from blood
islands

Blood Vessel and Blood Cell

Connection

Blood vessels and blood cells are believed to share a common

precursor, the hemangioblast.

Mutations of certain transcription factors in mice and

zebrafish will delete both blood cells and blood vessels.

The earliest blood cells and the earliest capillary cells share
many of the same rare proteins on their cell surfaces

A hemangioblast

Two Processes of Blood Construction

vasculogenesis

blood vessels are created de novo from the lateral plate

mesoderm

Phases:

First phase: groups of splanchnic mesoderm

cells
are
specified
to
become
hemangioblasts, the precursors of both the
blood cells and the blood vessel
Second phase: the angioblasts multiply and
differentiate into endothelial cells, which
form the lining of the blood vessels
Third phase: endothelial cells form tubes
and connect to form the primary capillary
plexus, a network of capillaries

angiogenesis
this primary network will be
remodeled and pruned into a
distinct capillary bed, arteries, and
vein
Step by step:
VEGF acting alone on the newly formed capillaries
causes a loosening of cell contacts and a degradation
of the extracellular matrix at certain points.
The exposed endothelial cells proliferate and sprout
from these regions, eventually forming a new vessel.
The mature capillary network forms and is stabilized
by TGF- and platelet-derived growth factor

Two Processes of Blood Construction

Hemangioblasts
the
aggregation
of
hemangioblasts
in
extraembryonic regions is
acritical step in amniote
development, for the blood
islands that line the yolk sac
produce
the
vitelline
(omphalomesenteric) veins
that bring nutrients to the
embryo and transport gases
to central
and cells
fromof the
theblood
sites
of differentiate into the embryonic blood cells. As the blood
The
islands
islands
grow, they
eventually merge to form the capillary network draining into the two vitelline
respiratory
exchange.
veins, which bring food and blood cells to the newly formed heart.

Three growth factors may be responsible for

initiating vasculogenesis
basic fibroblast growth factor (FGF2)
required for the generation of hemangioblasts from the
splanchnic mesoderm

vascular endothelial growth factor (VEGF)

enable the differentiation of the angioblasts and their
multiplication to form endothelial tubes.

angiopoietin-1 (Ang1)
*Mutations
of either angiopoietin-1
or its between
receptor lead
to malformed
bloodcells
vessels,
deficient
mediates
the interaction
the
endothelial
and
the
in the smooth muscles that usually surround them

pericytes