web hosting short URLs photo sharing

Angiogenesis

The fetal circulation is one of the first organ systems to need to be able to function properly in order to sustain the fetus. Before a circulatory system has developed, nutrients and oxygen diffuse through the extraembryonic coelem and yolk sac from the placenta. As the embryo increases in size, its nutrient needs increase and the amount of tissue easily reached by diffusion decreases. Hence the circulation must develop quickly and accurately.

Development of the fetal circulation begins with the coalescing of angioblasts in the mesenchyme of the yolk sac. This occurs at about day 17. Following this, on day 18, angioblasts begin to coalesce into blood island in the splanchopleuric mesoderm of the embryo. The angioblasts in the blood islands flatten into endothelial cells. These join to form networks of endothelial channels that form the primitive circulatory system.

Hematogenesis

Blood cells themselves begin to be formed at about three weeks in the yolk sac and at about five weeks in the embryo. Although the source of the original stem cells that begin hematopoesis is unclear blood cell production is known to spread in the embryo through various organs. These include the liver, spleen thymus and finally the bone marrow.

Basic vascular system

By the end of the third week the so-called endothelial heart tubes have fused to form a single heart tube. The cardiovascular system consists of two dorsal aortae that, at the cranial end of the embryo, loop back on themselves to join the endothelial heart tubes. At the caudal end they branch to form a pair of umbilical arteries and a set of vitelline arteries to the yolk sac. Dorsolaterally the dorsal aortae give off intersegmental branches between the somites (which are now developing either side of the neural crest).

A set of vitelline veins has formed from the vascular plexus on the yolk sac. These will enter the sinus venosus of the heart along with the anterior and posterior cardinal veins, which are also forming at this time. The anterior and posterior cardinal veins do not enter the sinus venosus directly but join on each side to form the common cardinal vein which then leads into the sinus venosus. A third pair of veins, the umbilical veins, also enter the sinus venosus. In the umbilical cord itself these are joined to form a single umbilical vein.

By day 22 the heart begins to beat and the embryo has a functional circulatory system.

Aortic Arches

The cranial end of the fused heart tube forms the aortic sac from which branches, in turn, several pairs of aortic arches. These aortic arches connect the aortic sac to the dorsal aortae. These arches form in thickenings of the mesenchyme known as the pharyngeal arches. The pharyngeal arches (that go on to form structures of the lower face and neck) can be viewed as equivalent to the arches the develop in fish and other protochordates to form the gills. In the human aortic arches form in positions equivalent to the pharyngeal arches 1,2,3,4 and 6. If a fifth arch develops at all it quickly regresses.

The first aortic arches are formed when the endocardial tubes are drawn into the thorax by embryonic folding between days 22 and 24. On day 26 a second pair of aortic arches are forming by a mixture of angiogenesis and vasculogenesis. At this point the first aortic arches regress completely. The third and fourth arches appear on day 28 while the first arches are regressing. On day 29 the sixth arch forms and the second pair of arches regress leaving just a small remnant to become the stapedial artery.

Arterial system remodelling

The third and fourth aortic arches become separate from each other by day 35 when the segments of dorsal aortae connecting them regress. The head is solely supplied by the cranial portions of the dorsal aortae, which are supplied through the third arches only, until the development from the third arch, of the carotid arteries. The common carotids are directly derived almost entirely from the third arches. The proximal part of the internal carotid arteries form from the far end of these vessels. The external carotid arteries are derived secondarily from the common carotids.

The fourth arch and a section of dorsal aorta goes on to form, on the respective side, the right subclavian artery. It connects through to the limb by joining with the 7th cervical intersegmental artery which grows into the limb bud The right dorsal aorta loses its connection with both the right sixth arch and the midline dorsal aorta. On the left side the fourth arch retains its connection to both the aortic sac and the dorsal aorta. In the adult it remains as a short section at the cranial end of the aortic arch.

The sixth arch disappears completely on the right side. On the left the sixth arch normally remains patent until birth. This is the ductus arteriosus. Until the infant breathes for the first time the lungs have a very high resistance to bloodflow. The ductus arteriosus allows adequate bloodflow to the rest of the fetus. It normally closes at birth.

Although the vascular system developing in the lung buds eventually ends up connected to the sixth arch it is thought that initially the pulmonary arteries derive from the fourth arch. Their roots becoming connected to the sixth arch as they grow towards the lung and the connection to the fourth arch degenerates. The distal ends anastomose with vasculature forming in the mesenchyme surrounding the developing lung buds.

Venous system remodelling

The vitelline veins pass through the region in the developing embryo that will later become the liver. Hepatic cords in the developing liver anastomose around pre-existing endothelium-lined spaces. Later they become linked to the vitelline veins. The hepatic veins are formed from the remains of the right vitelline vein in the region of the liver. The portal vein from the anastomosis around the doudenum formed by the vitelline vein. The superior portion of the right vitelline vein goes on to form the terminal portion of the inferior vena cava whilst the rest of the vitelline system regresses. A single oblique channel also appears in the developing liver.

This is the ductus venosus and is an important shunt of blood from the umbilical system directly to the heart. In the umbilical system it is the right vein that disappears. The left umbilical vein loses its connection to the left sinus horn and forms an anastomosis with the ductus venosus. Oxygenated blood from the placenta thus reaches the heart directly via a single umbilical vein and the ductus venosus.

The cardinal veins go on to form a major portion of the thoraco-abdominal vasculature. During the eight week an anastomosis connects the left and right anterior cardinal veins. Blood shunts through it from left to right. The caudal end of the left anterior cardinal vein disappears leaving the anastomosis which will become the left brachiocephalic vein. The right anterior cardinal vein degenerates as well and goes on, along with the common cardinal vein, to form the superior vena cava.

In the adult the posterior cardinal veins have all but disappeared. The only remaining derivatives are the common iliac vein and the root of the azygos vein. Two additional pairs of veins form to replace the posterior cardinal veins at a later stage. These are the subcardinal and supracardinal veins and they develop medial to the posterior cardinal veins. The subcardinal veins will eventually drain the region of the kidneys and the gonads. The supracardinals will give rise to another portion of the inferior vena cava and to the azygos system.

Fetal circulation

Oxygenated blood is delivered to the fetus through the umbilical vein. About 50% travels straight to the heart through the ductus venosus and the other 50% passes through the hepatic sinusoids. A sphincter operates to control the balance of blood flow between the ductus venosus or through the hepatic sinusoids. This prevents overloading of the heart when there is high venous flow in the umbilical vein, for example, in uterine contraction.

The blood enters the right atrium through the inferior vena cava. In the inferior vena cava the oxygenated blood is mixed with deoxygenated blood from the lower limbs, abdomen and pelvis and so loses a little of its oxygen tension. On entering the right atrium the main flow of the blood is directed by the crista dividens (inferior border) of the septum secundum through the foramen ovale into the left atrium. It mixes here with a little de-oxygenated blood from the lungs and then travels through to the left ventricle to be pumped up through the aorta. The arteries supplying the heart, head, neck and upper limbs are supplied by well-oxygenated blood from the ascending aorta.

The superior vena cava supplies de-oxygenated blood to the right atrium. This mixes with a little of the well-oxygenated blood from the umbilical vein and then passes through into the right ventricle. From the right ventricle this blood is pumped through to the pulmonary trunk. Here, a little blood flows through to the lungs (about 5 to 10 % of total cardiac output). Because in uterine life the lungs do not need to function they are supplied with only enough blood to keep them alive and developing. The remainder of the blood in the pulmonary trunk in passed through to the aorta via the ductus arteriosus. The blood in the descending aorta is then split between that which is returned to the placenta for re-oxygenation and that which is passed to the viscera and inferior half of the body.

Neo-natal circulation

Once the infant is born the priorities of circulation change dramatically. There is no longer a need for a blood supply through the umbilical vein. However, with (hopefully) a set of working lungs there is a need for all the blood to be passed through the pulmonary circulation. In the first few breaths this change over is achieved. The stretching of the pulmonary arteries and the opening of them as air is drawn into the lung causes a sudden drop in pressure in the right atrium. Reversal of the pressure difference between the left and right atria causes the foramen ovale to shut. This will not be a permanent state of affairs until the end of the third month. The lowering of right atrial pressure is also helped by the occlusion of the ductus venosus as its sphincter constricts.

Also closing at birth is the ductus arteriosus (although this may remain patent for two or three months after birth).. Constriction of the ductus is mediated by bradykinin released from the lungs on their initial inflation. The effects of bradykinin are dependent on the PO₂ in the blood passing through it. Once this reaches about 50mmHg then the ductus will close. Prostaglandins, released when the oxygen content is low as in fetal life, maintain an open ductus arteriosus. Inhibitors of their synthesis can cause closure of the ductus in premature infants.

The final vessels to completely occlude in the transfer between fetal and infantile circulations are the umbilical arteries and veins. At birth the umbilical arteries constrict rapidly, preventing loss of the infants' blood. For a minute or so afterwards the umbilical vein remains patent and fetal blood is transferred out of the placenta to the infant.

The closed vessels of the infant develop into several noticeable structures in the adult. The umbilical vein degenerates into the ligamentum teres. This can remain patent for a very long time and is used for giving fetal blood transfusions. Most of the other parts of the umbilical arteries become the medial umbilical ligaments.

The ductus arteriosus is normally anatomically closed by the twelfth week after parturition. It degenerates to form the ligamentum arteriosum.

Thus the new-born infant is left with the adult pattern of circulation where de-oxygenated blood enters the right atrium and is pumped through the right ventricle to the pulmonary arteries. In the lungs it is oxygenated to be returned to the left atrium of the heart via the pulmonary veins. Oxygenated blood can then be pumped to all parts of the body by the left ventricle. It is interesting to note that in the fetus, the right ventricle has had more work to do and thus has a thicker wall. Once the left ventricle takes over the majority of work. It quickly hypertrophies’ as the right ventricle atrophies through reduced work. Thus the normal adult pattern of the heart is also only finally developed after birth.

(c)1998 Nick Manville