The Formation and Function of Blood Vessels, Lymphatic System, and Circulation

Blood vessels undergo development through two mechanisms: vasculogenesis, involving the union of angioblasts, and angiogenesis, characterized by the budding of vessels from preexisting ones. Vasculogenesis primarily contributes to the formation of large vessels such as the dorsal aorta and cardinal veins, while the remaining vascular system develops later through angiogenesis. The orchestration of the entire vascular system is intricately influenced by factors such as vascular endothelial growth factor (VEGF) and other growth factors.

During the fourth and fifth weeks of development, pharyngeal arches form, each associated with a cranial nerve and an artery. Originating from the aortic sac, the most distal part of the arterial trunk, aortic arches are situated in the mesenchyme of the pharyngeal arches, terminating at the right and left dorsal aortas. While the dorsal aortas remain separate in the arch region, they fuse caudally to form a single vessel. Pharyngeal arches and their vessels develop sequentially in a cranio-caudal sequence, with each new arch giving rise to a branch, resulting in five pairs of arteries (the fifth pair either doesn't form or forms incompletely and regresses). Numbered I, II, III, IV, and VI, the disposition of these arches changes during development, and some vessels disappear.

The aortopulmonary septum division of the arterial trunk leads to the branching of the heart's efferent channel into the ventral aorta and pulmonary trunk. The aortic sac forms the right and left horns, later giving rise to the brachiocephalic artery and the proximal aortic arch segment.

The first aortic arch nearly disappears on day 27, leaving a small portion giving rise to the maxillary artery. The second arch disappears shortly after, forming the hyoid and stapedial arteries. The third aortic arch is voluminous, with the fourth and sixth arches still forming. Even though the sixth arch is incomplete, the primitive pulmonary artery is already present.

On day 29, the first two arches disappear, leaving the third, fourth, and sixth arches voluminous. The pair of sixth arches continues into the pulmonary trunk.

The initial symmetry of the aortic arch system vanishes, forming the final structure.

The common carotid artery and the initial part of the internal carotid artery derive from the third aortic arch. The external carotid artery forms by budding from the third aortic arch.

The fourth aortic arch persists on both sides, forming different structures. On the left, it forms the segment of the aortic arch between the emergence of the left common carotid artery and the left subclavian artery. On the right, it forms the most proximal segment of the right subclavian artery.

The fifth aortic arch may not form at all or may form incompletely and then regress.

The sixth aortic arch, or the pulmonary arch, gives rise to a branch extending toward the developing pulmonary primordium. On the right, the proximal portion becomes the proximal segment of the right pulmonary artery, and the distal portion disappears. On the left, the distal portion persists during intrauterine life as the ductus arteriosus.

The carotid duct between the third and fourth arches is obliterated, and the portion of the right dorsal aorta between the origin of the seventh intersegmental artery and the junction with the left dorsal aorta disappears.

Prosencephalon development, cephalic folding, and neck elongation shift the heart into the thoracic cavity. The carotid and brachiocephalic arteries elongate. The origin point of the left subclavian artery moves cranially, reaching near the origin of the left common carotid artery.

Due to the heart's caudal shift and the disappearance of different aortic arch portions, differences arise between the trajectories of the two recurrent laryngeal nerves, branches of the vagus nerve innervating the pair of sixth pharyngeal arches.

As the heart descends into the thoracic cavity, the laryngeal nerves encircle each corresponding sixth aortic arch, ascending again to the larynx, explaining their recurrent path. On the right, with the disappearance of the distal segments of the fifth and sixth aortic arches, the recurrent laryngeal nerve takes an ascending course around the right subclavian artery. On the left, the recurrent laryngeal nerve doesn't ascend because the distal portion of the sixth aortic arch persists as the ductus arteriosus, later becoming the ligamentum arteriosum.

Initially, the vitelline arteries begin as paired vessels supplying the yolk sac, eventually merging to become the arteries of the dorsal mesentery of the intestine. In adulthood, these arteries transform into the celiac artery, superior mesenteric artery, and inferior mesenteric artery, providing blood to structures derived from the proenteron, mesenteron, and metenteron, respectively.

The umbilical arteries, originally paired ventral branches of the dorsal aorta arising from the common iliac arteries, travel towards the placenta with the allantois. By the fourth week, each artery establishes a secondary connection with the dorsal branch of the aorta and the common iliac artery, leading to the disappearance of the initial origin area. After birth, the proximal segments of the umbilical arteries persist as the internal iliac and superior vesical arteries, while the distal segments undergo obliteration, forming the medial umbilical ligaments.

Coronary arteries originate from angioblasts produced in a separate region and are dispersed on the heart's surface through the migration of proepicardial cells or directly from the epicardium. Guided by the underlying myocardium, certain epicardial cells undergo a transformation from epithelial to mesenchymal cells, actively participating in the development of endothelial and smooth muscle cells within the coronary arteries. Additionally, neural crest cells from the proximal segments of these arteries contribute to the formation of smooth muscle cells. The connection between the coronary arteries and the aorta is established as endothelial cells from the coronary arteries extend into the aorta, effectively causing the coronary arteries to integrate with the aorta.

The venous system manifests in three primary systems during embryonic development: the vitelline system, giving rise to the portal venous system; the cardinal vein system, forming the inferior and superior vena cava systems; and the umbilical system, which ceases to exist after birth. Within the vena cava system, various malformations may occur, such as the left-sided position of the superior vena cava or the duplication of the inferior and superior vena cava.

By the fifth week, three main pairs of veins emerge: the vitelline veins or omphalo-mesenteric veins, responsible for transporting blood from the yolk sac to the venous sinus; the umbilical veins, originating from the chorionic villi and carrying oxygenated blood to the embryo; and the cardinal veins, facilitating the transportation of blood from the actual embryonic body.

Before entering the venous sinus, the vitelline veins establish a venous plexus around the duodenum and traverse the transverse septum. The presence of hepatic primordia within the septum disrupts the course of the veins, leading to the formation of an extensive venous network known as hepatic sinusoids. This interruption causes a redirection of blood from the left half of the liver to the right, resulting in a decrease in the dimensions of the left sinus horn and an increase in the caliber of the right vitelline vein, now referred to as the right hepatocardiac canal. This canal eventually forms the hepatocardiac segment of the inferior vena cava, while the proximal segment of the left vitelline vein regresses. The anastomotic network around the duodenum gives rise to the portal vein, and the right vitelline vein transforms into the superior mesenteric vein, draining blood from the primitive intestinal loop, while the distal portion of the left vitelline vein undergoes regression.

Initially positioned on either side of the liver, the umbilical veins establish contact with the hepatic sinusoids. Subsequently, the proximal segments of both umbilical veins and the right umbilical vein regress, leaving the left umbilical vein as the solitary vessel responsible for transporting blood from the placenta to the liver. The increased placental circulation between the left umbilical vein and the right hepatocardiac canal triggers the development of the ductus venosus, creating a direct route bypassing the hepatic sinusoidal plexus. Postnatally, both the left umbilical vein and the ductus venosus undergo obliteration, forming the round ligament of the liver and the venous ligament, respectively.

The cardinal veins, comprising anterior and posterior branches initially responsible for venous blood transport from the embryonic body, unite before entering the sinus venosus horn, forming common cardinal veins. Between the fifth and seventh weeks, the symmetrical cardinal vein system witnesses the emergence of subcardinal veins (transporting blood from the kidneys), sacrocardinal veins (conveying blood from the lower limbs), and supracardinal veins (receiving blood from the trunk wall via intercostal veins). Subsequently, anastomoses between the left and right halves of the venous system lead to the formation of the vena cava system, redirecting blood from the left to the right half of the body.

Noteworthy anastomoses include the left brachiocephalic vein arising from anastomosis between the anterior cardinal veins, facilitating the transport of blood from the left half of the head and left upper limb to the right side. The left superior intercostal vein persists from the terminal portion of the left posterior cardinal vein. The superior vena cava originates from the right common cardinal vein and the proximal segment of the right anterior cardinal vein.

Subcardinal veins anastomose to form the left renal vein, leading to the disappearance of the left subcardinal vein. The right subcardinal vein transforms into the renal segment of the inferior vena cava.

The anastomosis of sacrocardinal veins gives rise to the left common iliac vein, and the right sacrocardinal vein forms the sacrocardinal segment of the inferior vena cava. When the renal segment of the inferior vena cava merges with the hepatic segment from the right vitelline vein, the inferior vena cava, consisting of hepatic, renal, and sacrocardinal segments, achieves its complete formation.

Following the obliteration of the main segment of the posterior cardinal veins, the supracardinal veins become crucial in draining blood from the trunk wall. Intercostal veins from 4 to 11 contribute to the right supracardinal vein, forming the azygos vein. On the left side, intercostal veins from 4 to 7 drain into the left supracardinal vein, now known as the hemiazygos vein, which subsequently drains blood into the azygos vein.

As the embryo's nutritional needs rapidly increase, diffusion alone cannot provide sufficient support. This necessitates the development of a transport system comprising the heart, vessels, and the essential transport medium known as blood.

In terms of blood formation, it unfolds across three distinct periods: The Embryonic or megaloblastic period, the Fetal or hepatolienal period, and the Medullary period.

The megaloblastic period initiates between the 13th and 15th day. Blood cell genesis commences in the extraembryonic mesenchyme of the yolk sac, extending to the mesenchyme of the umbilical stalk and chorionic mesenchyme. Within island areas of mesenchymal cells, hemocytoblasts form, with those inside becoming proerythroblasts, while those outside transform into angioblasts, forming vascular walls.

Nucleated blood cells, termed proerythroblasts, emerge during this phase. Simultaneously, hematogenous island areas, serving as foci for blood and vascular formation, manifest in later stages.

Commencing at the end of the second month and extending until the eighth month, the hepatolienal period unfolds in the mesenchymal cells of the hepatic primordium. This phase witnesses the formation of primary erythrocytes (reticulocytes) and granulocyte precursors.

From the fourth month onward, the spleen actively contributes to the production of red and white blood cells. With birth, the activities associated with the hepatolienal period conclude, though under exceptional circumstances like chronic blood loss, these hematopoietic foci may be reactivated.

The medullary period initiates in the fifth month, persisting after birth. Up until birth, it encompasses the entire bone marrow, transforming into yellow bone marrow postnatally. Blood cell formation becomes confined to the red bone marrow within the epiphyses, as well as in flat and short bones.

Blood cell differentiation initiates with the basophilic hemocytoblast, originating from the mesenchymal cell. Through differential cell division, one daughter cell remains undifferentiated, while the other becomes a genetically determined precursor cell (progenitor cell). This cell serves as the origin for erythrocytes, granulocytes, monocytes, and thrombocytes during the medullary period.

Erythrocytes develop from hemocytoblasts, progressing through strongly basophilic proerythroblasts and erythroblasts. Surrounding reticular cells provide iron for hemoglobin formation, transforming the erythroblast into an acidophilic normoblast. After mitotic divisions, pyknotic cellular nucleus expulsion results in reticulocytes. Maturation to the erythrocyte stage takes approximately three days.

Granulocytes originate from hemocytoblasts, passing through stages of basophilic myeloblasts, promyelocytes, and myelocytes. The myelocyte, initially basophilic, becomes enriched with azurophilic granules. Specific neutrophil, eosinophil, or basophil granules alter the cytoplasm's basophilic character. The cellular nucleus elongates, leading to the metamyelocyte. Further nuclear subdivision and chromatin condensation yield the segmented granulocyte.

Monocytes form from promyelocytes, transforming into monoblasts. Lymphocytes also derive from bone marrow cells, with some migrating to the thymus, and others to lymphatic organs. T lymphocytes develop cellular immunity in the thymus, while B lymphocytes, carriers of humoral immunity, form in other lymphatic organs. B lymphocyte immune maturation likely occurs in the bone marrow, with lymphoblasts as precursors.

Platelets form through cytoplasmic divisions in bone marrow megakaryocytes, originating from polilobate polypoid megakaryoblasts. Blood vessel and heart development correlate closely in both function and time. The embryonic disc's lengthwise bending forms the first vascular primordia through blood island confluence in extraembryonic mesenchyme during the third week. Initially appearing in three locations—the dorsal wall of the yolk sac, umbilical stalk mesenchyme, and chorionic mesenchyme.

The formation of vascular primordia by angioblasts initiates the creation of small endothelial canaliculi. The yolk sac's initial circulatory system, developed with the onset of the cardiac pulse, connects vitelline vessels from the extraembryonic mesenchyme of the yolk sac to the embryo's vessels. After the yolk sac's nutrient reserves deplete, vitelline vessels undergo obliteration. The hepatic primordium encompasses part of the vitelline vein, and from the vitelline arteries, the celiac trunk, superior mesenteric artery, and inferior mesenteric artery arise.

The placental circulatory system replaces the yolk sac's system. Allantoic vessels connect with chorionic villi and the embryo's dorsal aortas, forming the umbilical vessels. The right umbilical vein obliterates, leaving the functional left umbilical vein. This vein partially conducts blood from the placenta to the liver and bypasses the hepatic circulatory system through the ductus venosus into the inferior vena cava.

The intraembryonic circulatory system begins with the development of vessel primordia and the endocardial tube shortly before the formation of the first somites. Under initial pulsations, diffuse vessel networks merge into larger vessels. Dorsal aortas arise on both sides, connecting extra- and intraembryonic vessels.

Blood from the endocardial tube travels through the ascending ventral aorta into dorsal aortas via branchial arch arteries, returning to the heart through precardinal and postcardinal veins. The anterior and posterior cardinal veins, along with the umbilical and vitelline veins, drain into the heart's venous sinus.

It's crucial to differentiate between angiogenesis and vasculogenesis in the embryonic circulatory system formation. Angiogenesis involves budding, as observed in the central nervous system vessels, while vasculogenesis entails in situ vessel formation with local mesenchymal cell recruitment, particularly visible in the splanchnopleure.

Before birth, oxygen-saturated blood from the placenta returns via the umbilical vein to fetal circulation. Most of this blood bypasses the liver through the ductus venosus into the inferior vena cava. Fetal blood, rich in oxygen, enters the right atrium and is directed toward the foramen ovale. From the left atrium, the blood enters the left ventricle, ascending aorta, and reaches the myocardium and cerebral tissue. Deoxygenated blood from the superior vena cava flows through the right ventricle and pulmonary trunk, mostly passing through the ductus arteriosus into the descending aorta. After circulating through the descending aorta, blood reaches the placenta through the umbilical arteries, with an oxygen saturation of approximately 58%.

The oxygen content of blood in the umbilical vein gradually decreases during circulation to fetal organs, mixing with deoxygenated blood at various points, including the liver, inferior vena cava, right atrium, left atrium, and the junction of the ductus arteriosus with the descending aorta.

During the prenatal period, fetal oxygen supply is ensured by placental circulation. Following birth, gas exchanges shift to the pulmonary system. In the initial months post-birth, several circulatory changes take place: closure of the ductus arteriosus and foramen ovale, and the closure of the umbilical vein and ductus venosus, forming the round ligament of the liver and the ligamentum venosum. Additionally, the umbilical arteries form the medial umbilical ligaments.

The circulatory alterations at birth stem from the cessation of placental blood flow and the initiation of breathing. The closure of the ductus arteriosus results from the contraction of its muscular wall, leading to increased left atrium pressure. Simultaneously, the right atrium experiences decreased pressure due to the halt in placental blood flow, causing the primary and secondary septa to unite and close the foramen ovale.

Closure of the umbilical arteries is likely induced by thermal and mechanical stimuli and changes in oxygen partial pressure, causing the contraction of their smooth muscle walls. While the arteries close within minutes after birth, complete obliteration of the lumen by fibrous tissue deposition takes 2 to 3 months. The distal segments form the medial umbilical ligaments, while the proximal segments remain patent, forming the superior vesical arteries. Post-closure, the umbilical vein and ductus venosus also close, yet placental blood continues to enter the newborn's circulation for a brief period. The obliterated umbilical vein forms the round ligament of the liver, located at the lower edge of the falciform ligament, and the ductus venosus forms the ligamentum venosum.

The ductus arteriosus closes almost immediately after birth due to the contraction of its smooth muscle layer, mediated by bradykinin released by the lungs during initial distension. Total anatomical obliteration through intimal proliferation takes 1 to 3 months, forming the arterial ligament in adults.

Foramen ovale closure results from increased left atrium pressure and decreased pressure in the right heart. The first breath compresses the primary septum against the secondary septum. Although reversible in the early days of life, crying causes a right-to-left shunt, leading to cyanotic episodes. Constant apposition gradually leads to septal fusion around the age of 1 year. In approximately 20% of individuals, perfect anatomical closure is unattainable (patent foramen ovale).

The lymphatic system, responsible for draining interstitial fluid or lymph, emerges in all vertebrates through vessels initially formed in the mesenchyme as endothelium-lined spaces.

Unlike the cardiovascular system, the lymphatic system's development begins after the fifth week of gestation. Lymphatic vessels arise either from mesenchyme in situ or as sac-like evaginations of venous endothelium. The formation includes six primary lymphatic sacs: two jugular (at the junctions of subclavian and anterior cardinal veins), two iliac (at the junctions of iliac and posterior cardinal veins), one retroperitoneal (near the mesentery root), and one cisterna chyli (dorsally to the retroperitoneal sac). Interconnected vessels link these sacs, draining lymph from limbs, trunk, head, and neck. An anastomosis connects the jugular lymphatic sacs to the cisterna chyli, forming the right and left thoracic ducts and two main channels. The thoracic duct develops from the distal portion of the right thoracic duct, anastomosis, and cranial part of the left thoracic duct. The right lymphatic duct forms from the cranial part of the right thoracic duct. Both ducts maintain connections with the venous system and drain into the junction between internal jugular and subclavian veins, with the thoracic duct's final form varying due to numerous anastomoses.

Primary lymphatic ganglia appear in the third month after the fragmentation of lymphatic sacs. Secondary ganglia develop along the afferent vessels, with initial formations in axillary and inguinal regions. Lymphatic plexuses interact with mesenchymal trabeculae, forming a nodular lymphatic network through proliferation and differentiation. Surrounding nodes, lymphatic vessels anastomose, creating the marginal sinus and becoming afferent vessels. A connective tissue capsule envelops the marginal sinus, and within the node, cortex and medulla differentiate. Channels originate from the marginal sinus, traverse the medulla to form the central sinus near the hilum, and give rise to efferent vessels. The endothelium lining these channels and sinuses generates lymphocytes, organizing them into lymph nodes, with contributions from some lymphocytes originating from the thymus.

During lymphatic system development, anomalies such as the thoracic duct's origin from a lymphatic plexus, double thoracic duct, congenital lymphedema due to dilated lymphatic channels, cystic lymphangioma, and congenital hypoplasia of lymphatic vessels may occur.

References

1. Anatomia Omului, Volumul I: Embriologie; Semestrul I; Prof. univ. dr. med. Andrei Motoc; Editura „Victor Babeș”, Timișoara, 2018

2. Embriologie - Sinteze didactice; Romeo Chiriac, Anca Indrei ;Editura Fundatiei Chemarea, Iasi, 1997

3. Embriologie Umană; Lidia Chircor, Loredana Surdu;Editura Ex Ponto, Constanța, 2014

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