development of cvs - 2 OF 2 - final.pptx

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1. DEVELOPMENT OF THE HEART AND THE GREAT VESSELS Under the guidance of the CTVS Dept Divine Heart & Multispecialty Hospital Dr (Prof) A K Srivastava Dr Manoj Kumar Dr Mayank Jadon Presenter :- Dr Sandeep Kumar DrNB  CVTS JR-1 Batch 2023

2. When the embryo is no longer able to satisfy its nutritional requirements by diffusion, Then the cardio vascular system starts to develop in middle of 3rd week of gestation.

3. SCHEME OF THE CVS EMBRYOLOGY ESTABLISHMENT AND PATTERNING OF THE PRIMARY HEART FIELD FORMATION AND POSITION OF THE HEART TUBE FORMATION OF THE CARDIAC LOOP MOLECULAR REGULATION OF CARDIAC DEVELOPMENT DEVELOPMENT OF THE SINUS VENOSUS FORMATION OF THE CARDIAC SEPTA FORMATION OF THE CONDUCTING SYSTEM OF THE HEART VASCULAR DEVELOPMENT CIRCULATION BEFORE AND AFTER BIRTH

4. ESTABLISHMENT AND PATTERNING OF THE PRIMARY HEART FIELD Progenitor heart cells (Epiblast, near cranial end of primitive streak) migrate (16th day POG) through streak and into the visceral layer of lateral plate mesoderm and form horseshoe shaped cluster called primary heart field (PHF) cranial to the neural folds. Secondary heart field (SHF) resides in visceral (splanchnic) mesoderm ventral to pharynx.

5. Heart fields are specified on both sides from lateral to medial to become the different parts of the heart. PHF forms part of the atria and the entire left ventricle. SHF  forms the right ventricle and outflow tract (conus cordis and truncus arteriosus) and formation of the atria at the caudal end of the heart. Patterning of these cells occur about the same time that laterality is being established for the entire embryo, and this process and the signaling pathway it is dependent upon are essential for normal heart development.

6. HF's are induced by underlying pharyngeal endoderm to form cardiac myoblast and blood islands (blood cells and vessels). Islands unite and form a horseshoe-shaped endothelial lined tube surrounded by myoblasts. This is cardiogenic region and the intraembryonic cavity over it, later develops into the pericardial cavity. Nearby islands (bilaterally, parallel and close to midline) develops into a pair of longitudinal vessels, the dorsal aortae.

7. FORMATION AND POSITION OF THE HEART TUBE Initially , the central portion of the cardiogenic area is anterior to the oropharyngeal membrane and the neural plate. After the closure of the neural tube and formation of the brain vesicles, the CNS grows rapidly towards cranially and extends over central cardiogenic region. As a result of brain growth and cephalic folding of the embryo, the oropharyngeal membrane pulled forward, and the heart and pericardial cavity moves first to cervical region and finally to the thorax.

8. As the embryo grows and bends cephalocaudally, it folds laterally and caudal regions of paired cardiac tube merges except at their caudal most ends. Simultaneously, the central part of the horseshoe-shaped tube expands to form the future outflow tract and ventricular regions. Heart becomes continuous expanded tube consisting of 2 layers, receives blood from caudal pole and begins to pump blood out of the first aortic arch into the dorsal aorta at its cranial pole. The developing and bulging heart tubes initially attached to dorsal side of pericardial cavity by dorsal mesocardium (derived from SHF), later disappears and create transverse pericardial sinus, which connects both pericardium. No ventral mesocardium* Now heart is suspended in the cavity by blood vessels at its cranial and caudal poles.

9. Myocardium thickens and secrets a layer of extracellular matrix, rich in hyaluronic acid, called cardiac jelly towards the endocardium. Mesenchymal cells from dorsal mesocardium (at caudal end) proliferate and migrate over the surface of the myocardium to form the epicardial layer of the heart tube. Now the heart tube consist of three layers and the outer layer is responsible for formation of the coronary arteries, including their endothelial lining and smooth muscles.

10. FORMATION OF THE CARDIAC LOOP The heart tube continues to elongate due to new cells added by SHF's at its cranial end. The lengthening process is essential for formation of RV, outflow tract region and for the looping process. If this inhibited than a variety of outflow tract defects occurs i.e. DORV, VSD, TOF, PA and PS etc. On day 23 the cardiac tube begins to bend:- cephalic end – bends ventrally, caudally and to the right caudal end – shifts dorso -cranially and to the left. Bending creates the cardiac loop and is completed by day 28.

11. The atrial portion, initially a paired structure outside the pericardial cavity, forms a common atrium and is incorporated into the pericardial cavity. The atrioventricular junction remains narrow and forms the atrioventricular canal Bulbus cordis is narrow except for its proximal third and will form the trabeculated part of the right ventricle. Middle third, the conus cordis will form outflow tract for both ventricles. Distal third, the truncus arteriosus will forms roots and proximal portion of the aorta and pulmonary artery. The junction between the ventricle and the bulbus cordis, externally indicated by the bulbo -ventricular sulcus, remains narrow, called the primary interventricular foramen.

12. When looping is complete , the smooth walled heart tubes begins to form primitive trabeculae in two sharply defined area just proximal and distal to the primary interventricular foramen. Bulbus temporary remains smooth walled. Primitive ventricle --> now primitive left ventricle. Proximal third of bulbus cordis --> primitive right ventricle. Conotruncal portion of the heart tube shifts gradually from right side of pericardial cavity to a more medial position due to development of two transverse dilations of the atrium, bulging on each side of the bulbus cordis.

13. MOLECULAR REGULATION OF CARDIAC DEVELOPMENT Signals from anterior (cranial) endoderm induce a heart forming region in overlying visceral mesoderm by inducing the Transcription factor NKX2.5. signal require secretion of BMP 2 and 4 secreted by endoderm and lateral plate mesoderm. BMP also upregulates expression of FGF8 that is important for the expression of cardiac specific proteins. WNT proteins (3a and 8) secreted by neural tube- inhibit heart development, must be blocked by inhibitors (CRESCENT and CERBERUS) which are produced by endodermal cells immediately adjacent to heart-forming mesoderm in the anterior half of the embryo. Above activity causes expression of NKX2.5, the master gene for heart development.

14. The venous portion is specified by retinoic acid (RA) produced by mesoderm adjacent to the presumptive sinus venosus and atria. Following the initial exposure to RA, these structures express the gene for retinaldehyde dehydrogenase, which allows them to make their own RA and commits them to becoming caudal cardiac structures. TBX5 is a transcription factor that contain a DNA binding motif known as the T-box. Expressed later than NKX2.5, it plays an important role in septation. Cardiac looping is dependent upon several factors, including the laterality pathway and expression of the transcription factor PITX2 in lateral plate mesoderm on the left side. HAND1 and HAND2, under the regulation of NKX2.5, contribute to expansion and differentiation of the ventricles.

15. SONIC HEDGEHOG (SHH) expressed by pharyngeal arch endoderm, regulates lengthening of the outflow tract by the SHF. NOTCH signaling through its ligand JAG1 is responsible for upregulation of FGFs in the SHF that in turn regulates migration and differentiation of neural crest cells essential for outflow tract septation and for development and patterning of the aortic arches. Mutation in SHH, NOTCH and JAG1 are responsible for some outflow tract, aortic arch and cardiac defects.

16. DEVELOPMENT OF THE SINUS VENOSUS In the middle of the fourth week, the sinus venosus receives venous blood from the right and left sinus horns. Each horn receives blood from three important veins: 1) the vitelline / omphalomesenteric vein, 2) the umbilical vein, 3) the common cardinal vein. At first, communication between the sinus and the atrium is wide, later the entrance of the sinus shifts to the right, which is primarily caused by left-to-right shunts of blood, which occurs in the venous system during the fourth and fifth weeks of development.

17. During the fifth week, obliteration of right umbilical vein and left vitelline vein, the left sinus horn loses its importance, and during 10th week, with the obliteration of left common cardinal vein, all that remains of the left sinus horn is the oblique vein of the left atrium and the coronary sinus. As a result of left-to-right shunt of blood, the right sinus horn and veins enlarges. The right horn is incorporated into the right atrium to form the smooth-walled part of RA. The sinoatrial orifice, is flanked on each side by a valvular fold, the right and left venous valves. Dorsocranially the valve fuses and form a ridge known as septum spurium . After incorporation of right sinus horn in RA, the left venous valve and the septum spurium fuse with the developing atrial septum.

18. Right venous valve – superior portion disappears entirely and inferior portion develops into two parts: 1) the valve of the inferior vena cava 2) the valve of the coronary sinus Crista terminalis forms the dividing line between the original trabeculated part of right atrium and the smooth walled part (sinus venarum ), which originated from the right sinus horn.

19. FORMATION OF THE CARDIAC SEPTA Formed between 27th and 37th days of development. One method by which a septa formed involve two actively growing masses of tissues that approach each other until they fuse, dividing the lumen into two separate canals. Such a septum may form by active growth of a single tissue mass, formation of such tissue mass, called endocardial cushions, depends on synthesis and deposition of extracellular matrices and cell migration and proliferation. These endocardial cushion protrusions develop in the atrioventricular and conotruncal regions, and in these locations, they assist in formation of atrial and ventricular ( memb ) septa , the AV canals and valves and the aortic and pulmonary channels .

20. Eventually cushion are populated by cell migrating and proliferating into the matrix: In AV cushions, cells are derived from overlying endocardial cells that detach from their neighbors and move into the matrix. In conotruncal cushions, cells are derived from neural crest cells migrating from the cranial neural folds to the outflow tract region. Because of the key locations, abnormalities in endocardial cushion formation may cause cardiac malformations, including ASDs and VSDs and defects involving the great vessels (transposition of great vessels, common truncus arteriosus and tetralogy of fallot ).

21. Septum formation in the common atrium At the end of 4th week, a sickle-shaped crest grows from the roof of the common atrium into the lumen. Ostium primum Programmed cell death (apoptosis) Ostium secundum Absorption of right horn of sinus venosus Foramen ovale Septum primum --> valve of FO After birth, when lung circulation begins and LA pressure increases Probe patency of foramen ovale .

22. Formation of left atrium and pulmonary vein Mesenchyme of dorsal mesocardium begins to proliferate and forms the dorsal mesenchymal protrusion (DMP) and this tissue grows with the septum primum towards the AV canal. DMP contain developing pulmonary vein, positioned in the left atrium by the growth and movement of DMP. Portion of the DMP at the tip of septum primum contributes to endocardial cushion formation in AV canal. The main stem of PV send 2 branches to each lung, after incorporation into the left atrium there are four separate openings for PV into the LA.

23. Septum formation in atrioventricular canal At the end of the fourth week – 4 AV endocardial cushion develops as 2 lateral, 1 dorsal and 1 ventral border of AV canal. AV canal is accessible to primitive left ventricle and separated from the bulbus cordis by the bulbo ( cono ) ventricular flange. Near the end of fifth week the posterior extremity of flange disappears and the blood passing through AV canal now has direct access to the primitive left as well as the primitive right ventricle. The dorsal and ventral endocardial cushions further develops into the and fuse, resulting in a complete division of the canal inth right and left AV orifices by the end of the fifth week.

24. Atrioventricular valves After the fusion of endocardial cushions, each AV orifice is surrounded by local proliferations of mesenchymal tissue derived from the cushions itself. Bloodstream hollows out and thins tissue on the ventricular surface of these proliferations, the mesenchymal tissue becomes fibrous and forms the AV valves, which reman attached to the ventricular wall by muscular cords, these cords degenerate and replaced by dense connective tissue. The valves then consist of connective tissue covered by endocardium, they are connected to thick muscular trabeculae (papillary muscles) by means of chordae tendineae. 2 leaflet (bicuspid / mitral) - on the left side 3 leaflet (tricuspid) - on the right side

25. Septum formation in the truncus arteriosus and conus cordis During the fifth week – pairs of opposing ridges (truncal swelling / cushions) appears in the truncus, right superior and left inferior truncal swelling. Grows distally and toward opposite side, later on these ridges fuse and form aorticopulmonary septum, with spiral course. Concomitantly, similar swellings develop along the right dorsal and left ventral walls of conus cordis, grow towards each other and distally, to unite with the trucal septum. After fusion, the septum divides the conus into an anterolateral portion (RVOT) and a posteromedial portion (LVOT).

26. Cardiac neural crest cells : originated in the neural folds of hind brain, proliferate and migrate through 3, 4 and 6 pharyngeal arches, invade outflow region of the heart. Contributes to endocardial cushion formation in both the conus cordis and truncus arteriosus. Migration and proliferation is regulated by SHF through the NOTCH signaling pathway. Insult to SHF or cardiac neural crest cells causes disrupt formation of conotruncal septum and outflow defect occurs such as TOF, PS, PTA and TGA. Also contribute to the craniofacial development, facial and cardiac abnormalities can happen in same individual.

27. Septum formation in the ventricles By the end of the fourth week: two primitive ventricles begin to expand due to myocardial growth outside and continuous diverticulation and trabecula formation inside. The medial wall of expanding ventricles become apposed and gradually merge, forming the muscular interventricular septum, leaving behind an apical space between fused endocardial cushion and free rim of interventricular septum. Aka interventricular foremen, shrinks on completion of the conus septum and outgrowth of the tissue from the ventral endocardial cushion. Complete closure of the foramen forms the membranous part of the interventricular septum.

28. Semilunar valves After partition of the truncus, primordia of the semilunar valves becomes visible as small tubercles found on the main truncus swellings. One of each pair is assigned to the pulmonary and aortic channels respectively. A third tubercle appears opposite to fused trunal swellings in both cannels. Tubercles hollow out at their upper surface, forming the semilunar valves. Recent studies shows the involvement of neural crest cells in developing semilunar valves.

29. FORMATION OF THE CONDUCTING SYSTEM OF THE HEART Initially all myocardial cells in the heart tube have pacemaker activity and begins to beat at approximately 21 days of gestation. Soon the pacemaker activity is restricted to the caudal part of the left side of the cardiac tube. Later, the sinus venosus assumes this function and as the sinus is incorporated into the right atrium, pacemaker tissue lies near the opening of the superior vena cava. Thus the sinoatrial node (SAN) is formed. The atrioventricular node (AVN) begins as a collection of cells located around the atrioventricular canal that coalesce to form the AVN.

30. Impulse from the AVN pass to the atrioventricular bundle and left and right bundle branches and finally to the purkinje fibre network surrounding and activating the ventricles. Except for  sympathetic  and para sympathetic nerve fibres that terminates on SAN to regulate heart rate, all of the cells for heart's conduction system are derived from primary cardiac myocytes. Expression of TBX3 inhibits differentiation of these primary myocytes into ventricular muscle cells and allows them instead to differentiate into the conducting system.

31. VASCULAR DEVELOPMENT Blood vessel development by 2 mechanisms: 1) Vasculogenesis – by coalescence of angioblasts – dorsal aorta and cardinal veins. 2) Angiogenesis - sprout from existing vessels – remainder of vascular system. The entire system is patterned by involving VEGF and other growth factors.

32. ARTERIAL SYSTEM

33. AORTIC ARCHES Pharyngeal arches forms during the fourth and fifth weeks, each receives its own  cranial nerve and artery (aortic arches). Aortic arches arise from the aortic sac (the most distal part of truncus arteriosus) and embedded in mesenchyme of the pharyngeal arches and terminate in the right and left dorsal aortae. The pharyngeal arches and their vessels appear in a craniocaudal sequence, so that they are not all present simultaneously.

34. The aortic sac contributes a branch to each new arch as it forms, giving rise to a total of five pairs of arteries (I, II, III, IV and VI). During further development, this arterial pattern becomes modified, and some vessels regress completely.

35. Neural crest cells contribute the coverings(smooth muscle and connective tissue) of the pharyngeal arch vessels and regulate patterning of these vessels. Signals from the ectoderm and endoderm lining the arches provide interactive signals to NCC to regulate the patterning process. After division of truncus arteriosus into ventral aorta and the pulmonary trunk, the aortic sac then forms right and left horns, which subsequently give rise to the brachiocephalic artery and the proximal segment of the aortic arch, respectively.

36. Day 27 1st aortic arch disappears and remaining portion form the maxillary artery Soon the 2nd aortic arch also disappears and remaining portion form the hyoid and stapedial arteries The 3rd arch is large 4th and 6th arches are in the process of formation Even though the 6th aortic arch is not completed, the primitive pulmonary artery is already present as a major branch

37. Day 29 1st and 2nd aortic arches have disappeared 3rd, 4th and 6th aortic arches are large The conotruncal region has divided so that the sixth arches are now continuous with the pulmonary trunk. With further development, the aortic arch system loses its original symmetrical form and establishes the definitive pattern.

38. 3rd a ortic arch Forms the common carotid artery and the first part of the internal carotid artery. The remainder of the internal carotid is formed by the cranial portion of the dorsal aorta. The external carotid artery is a sprout of the 3rd aortic arch

39. 4th aortic arch Persist on both side but fate is different on both sides On the left :- part of the arch of the aorta, between the left common carotid and the left subclavian artery. On the right :- most proximal segment of the right subclavian artery. *the distal part is formed by a portion of the right dorsal aorta and the seventh intersegmental artery

40. 5th aortic arch Either never forms or forms incompletely and then regresses.

41. 6th aortic arch Aka pulmonary arch, gives off an important branch that grows toward the developing lung bud On the right side:- 1) proximal part – forms the proximal segment of the right pulmonary artery. 2) distal part – loses its connection with the dorsal aorta and disappears. On the left side:- Distal portion persist during intrauterine life as the ductus arteriosus.

42. Other changes Dorsal aorta between the entrance of the third and fourth arches, aka carotid duct, is obliterated The right dorsal aorta between the origin of the seventh intersegmental artery and the junction with the left dorsal aorta disappears When heart pushed into thoracic cavity, the carotid and brachiocephalic arteries elongates and the left subclavian artery, distally fixed in arm bud, shifts its point of origin from the level of seventh intersegmental artery to a higher point near the origin of left common carotid artery. The course of the RLN becomes different on the left and right side.

43. RLN These nerves, are branches of the vagus , supply the sixth pharyngeal arches. When the heart descends, they hook around the sixth aortic arches and ascends again to the larynx, which accounts for their recurrent course. On the right side:- distal part of the 6th and 5th aortic arch disappears, RLN moves up and hook around right subclavian artery On the left side:- distal part of sixth arch persist as ductus arteriosus, RLN doesn't move up.

44. VITELLINE AND UMBILICAL ARTERIES VITELLINE ARTERIES :- Paired vessels, supplying the yolk sac Fuse and form the arteries in the dorsal mesentery of the gut In the adult, represented by the Celiac and superior mesenteric arteries, supplying the foregut and midgut The inferior mesenteric arteries are derived from the umbilical arteries, supplying the hindgut.

45. UMBILICAL ARTERIES :- Paired ventral branches of the dorsal aorta, Course to the placenta in close association with allantois During the 4th week :- acquires a secondary connection with the dorsal branch of the aorta, the common iliac artery and loses its earliest origin After birth :- 1) proximal portion :- persist as the internal iliac and superior vesical arteries 2) distal portion :- obliterate and form the medial umbilical ligaments

46. CORONARY ARTERIES SHF --> dorsal mesocardium (caudal portion) --> proepicardial organ --> epicardium --> coronary arteries Underlying myocardium induces epithelial to mesenchymal transition of the epicardium. These mesenchymal cell contribute to endothelial and the smooth muscle cells NCC also contribute to smooth muscle formation in proximal coronaries and may direct connection to the aorta Connection occurs by the ingrowth of arterial endothelial cells from the arteries into the aorta causing the coronary arteries to invade the aorta

47. Arterial system defect Patent ductus arteriosus Coarctation of aorta

48. Abnormal origin of right subclavian artery

49. Double aortic arch

50. Right aortic arch Interrupted aortic arch

51. VENOUS SYSTEM

52. In the 5th week, 3 pairs of major vein develops The vitelline / omphalomesenteric veins :- carrying blood from the yolk sac to the sinus venosus The umbilical veins :- originating in the chorionic villi and carrying oxygenated blood to the embryo The cardinal veins :- draining the body of the embryo proper

53. VITELLINE VEINS From foregut and midgut to sinus venosus Form a plexus around the duodenum and pass through the septum transversum, the liver cords grow and interrupt the course of the veins and hepatic sinusoids forms As the left sinus horn reduces, blood from the left side of the liver is rechanneled toward the right, resulting in an enlargement of the right vitelline vein. The right hepatocardiac channel forms the hepatocardiac portion of the inferior vena cava

54. Left vitelline vein :- proximal and distal portion disappears The anastomotic network around the duodenum develops into a single vessel, the portal vein. The superior mesenteric vein, drains the primary intestinal loop, derives from the right vitelline vein.

55. UMBILICAL VEINS Passes on each side of the liver, some connects to hepatic sinusoids Proximal of both veins and distal of right umbilical vein also disappears, so distal part of left umbilical vein is left, which carry oxygenated blood from placenta to the liver. Increased placental circulation leads to formation of a direct channel from left umbilical vein to right hepatocardiac channel, the ductus venosus, bypassing sinusoidal plexus. After birth:- left umbilical vein --> ligamentum teres hepatis and ductus venosus --> ligamentum venosum.

56. CARDINAL VEINS Initially main venous drainage system of the embryo, consist of anterior and posterior cardinal veins, joins and form common cardinal veins and drains in the sinus horn of sinus venosus. During the 4th week, it's symmetrical. 5th to 7th week additional veins formed: 1) subcardinal veins - kidneys 2) sacrocardinal veins – lower extremities 3) supracardinal veins – body wall by the way of ICV, taking over the function of posterior cardinal vein.

57. Vena cava system formation Appearance of anastomosis between the left and the right in a manner that blood is channeled from left to right side. Anastomosis between the anterior cardinal veins develops and form the left brachiocephalic vein. Terminal portion of left posterior cardinal vein entering into left brachiocephalic vein is retained, the left superior intercostal vein (2nd and 3rd ICV's). The anterior cardinal veins, drain the head during 4th week and ultimately forms the internal jugular veins. External jugular veins, derives from venous plexus draining the face and side of the head.

58. SVC formed by right common cardinal vein and proximal portion of right anterior cardinal vein. Anastomosis between the subcardinal veins, develops and form the left renal vein, disappearing proximal portion of left subcardinal vein and distal portion remains as left gonadal vein, right subcardinal vein develops into renal segment of IVC. Anastomosis between the sacrocardinal veins, develops and form the left common iliac vein, right sacrocardinal vein becomes the sacrocardinal segment of the IVC. Right vitelline vein develops into hepatic segment of the IVC. All segment of the IVC connects and formation of IVC completes.

59. DEVELOPMENT OF THE AZYGOUS SYSTEM Major portion of the posterior cardinal veins obliterates and the supracardinal veins drains the body wall. On the right side :- 4th to 11th ICV empty into the right supracardinal vein, which along with a portion of posterior cardinal vein forms the azygous vein. On the left side :- 4th to 7th ICV enter into the left supracardinal vein, which forms the hemiazygous vein, emptying into the azygous vein.

60. Venous system defects Double inferior vena cava Absence of inferior vena cava

61. Left superior vena cava Double superior vena cava

62. CIRCULATION BEFORE AND AFTER BIRTH FETAL CIRCULATION

63. Umbilical vein gradually loses its high oxygen content as it Mixes with desaturate blood at following levels Liver, with portal system IVC, with extremities, pelvis and renal venous return Right atrium, with SVC (head and upper limb) Left atrium, with pulmonary veins Ductus arteriosus, from pulmonary artery to the descending aorta

64. CIRCULATORY CHANGES AT BIRTH Due to cessation of placental blood flow and the beginning of respiration. Closure of ductus arteriosus :- by contraction of its muscular wall, almost immediately after birth, flow into the pulmonary vasculature increases, results in pressure increase in the left atrium. Mediated by bradykinin released by lungs on initial inflation. Anatomical closure – 1 to 3 months. Forms ligamentum arteriosum.

65. With closure of placental blood flow, right atrial pressure decreases. Due to pressure change in both atrium the septum primum is then apposes to the septum secundum, resulting in functional closure of the foramen ovale . The first breath presses the septum primum against the septum secundum. During the first days it is reversible, crying causes right to left shunt, which accounts for cyanotic periods of newborn. Constant apposition causes fusion of two septa in about 1 year. In 20% perfect anatomical closure won't happen. (probe patent foramen ovale )

66. Closure of the umbilical arteries :- Thermal, mechanical and a change in oxygen tension causes contraction of the smooth musculature of the umbilical arteries. Functional closure - a few minutes after birth Anatomical closure – by fibrous proliferation take 2 to 3 months Proximal part – remain open as superior vesicle arteries Distal part – medial umbilical ligaments Closure of the umbilical vein and ductus venosus :- Shortly after that of umbilical arteries, hence blood from placenta may enter the newborn for some time after birth. Umbilical vein – ligamentum teres hepatis Ductus venosus – ligamentum venosum.

67. LYMPHATIC SYSTEM Develops after 5th week of gestation. Lymphatics arise as sac like outgrowths from the endothelium of veins. Six primary lymphatic sacs are formed :- 2 jugular – at junction of subclavian and anterior cardinal veins. 2 iliac – at junction of the iliac and posterior cardinal veins. 1 retroperitoneal – near the root of the mesentery. 1 cisterna chyli – dorsal to the retroperitoneal sac. Numerous channel connect the sacs with each other and drain lymph from the limbs, body wall, head and neck.

68. 2 prominent channels :- right and left thoracic ducts connects the jugular sac with cisterna chyli. Thoracic duct develop from caudal/distal part of right thoracic duct, cranial/proximal part of left thoracic duct and their anastomosis. The cranial/proximal part of right thoracic duct forms right lymphatic duct. Both of them maintain their original connections with the venous system and empty into the junction of the internal jugular and subclavian veins. Numerous anastomosis produce many variations in the final form of the thoracic duct.

69. Lymphatic lineage is regulated by transcription factor PROX1 and the upregulated gene is VEGFR3, which is the receptor for the paracrine factor VEGFC.