Cardiovascular System Development Notes

Vasculogenesis: Formation of blood vessels de novo from blood islands, which first appear at 3 weeks around the yolk sac and later in lateral plate mesoderm.
Angiogenesis: Sprouting of new blood vessels from pre-existing vessels.

Vasculogenesis vs Angiogenesis

Cardiogenic Field Establishment:
- Cardiac progenitor cells migrate from the epiblast through the primitive streak, positioning themselves rostral to the oropharyngeal membrane and neural folds within the splanchnic layer of lateral plate mesoderm.
- Cardiac progenitor cells differentiate into cardiac myoblasts.
- Vasculogenesis forms a horseshoe-shaped endothelial-lined tube surrounded by myoblasts; the overlying intraembryonic cavity develops into the pericardial cavity.

Heart Tube Position & Structure:
- Cephalic folding (driven by rapid CNS growth) pulls the cardiac tubes and pericardial cavity into the thorax.
- Lateral folding fuses the paired cardiac primordia into a single continuous heart tube.
- The heart tube wall consists of an inner endothelium, cardiac jelly, a muscular myocardium, and an outer epicardium (derived from migrating mesothelial cells).
Heart Tube Regions:
- Sinus venosus (venous inflow)
- Primitive atrium
- Primitive ventricle
- Bulbus cordis
- Truncus arteriosus (arterial outflow)

The Heart Tube

Cardiac Looping (Days 23–28):
- Cephalic portion (primitive ventricle and bulbus cordis) bends ventrally, caudally, and to the right.
- Caudal portion (atrial region) shifts dorso-cranially and to the left.
- Bulbus cordis components: proximal third forms the trabeculated part of the right ventricle; conus cordis forms outflow tracts of both ventricles; truncus arteriosus forms roots and proximal portions of the aorta and pulmonary artery.
Molecular Regulation:
- Secretion of $BMP\,2,4$ from cranial endoderm paired with $WNT$ inhibitors induces expression of the master gene $NKX2.5$ for cardiac differentiation.
- Looping depends on laterality genes $Nodal$ and $Lefty2$ .

Sinus Venosus Remodeling:
- Receives blood from vitelline, umbilical, and common cardinal veins.
- Left-to-right venous shunt during weeks 4–5 causes the left sinus horn to regress into the oblique vein of the left atrium and the coronary sinus.
- The right sinus horn enlarges and incorporates into the right atrium as the smooth-walled sinus venarum, separated from the original trabeculated atrium by the crista terminalis.
Atrial Septation:
- Septum primum: A sickle-shaped crest growing from the roof toward the endocardial cushions, leaving an opening called the $ostium\,primum$ . Cell death in the upper septum primum forms the $ostium\,secundum$ before the $ostium\,primum$ closes.
- Septum secundum: A secondary crescentic fold forming to the right of septum primum. It covers the $ostium\,secundum$ incompletely, leaving a flap-valve opening called the foramen ovale.
Left Atrium Differentiation:
- Smooth-walled posterior wall forms by incorporation of the single embryonic pulmonary vein and its 4 primary branches.

Atrioventricular Canal & Valves:
- Superior (anterior) and inferior (posterior) atrioventricular endocardial cushions fuse to divide the AV canal into right and left AV orifices.
- Proliferating mesenchymal tissue thins out via blood flow to form the bicuspid (mitral) valve on the left and tricuspid valve on the right, anchored to papillary muscles by chordae tendineae.
Ventricular Septation:
- Muscular interventricular septum expands upward from the ventricular floor.
- Temporary interventricular foramen closes via the membranous part of the interventricular septum, formed by growth from the inferior endocardial cushion and conus septum.
Conotruncal Septation:
- Spiral aorticopulmonary septum forms from fused right superior and left inferior truncal swellings and conus cushions, requiring neural crest cell migration through pharyngeal arches 3, 4, and 6.
- Divides outflow tracts into the anterolateral pulmonary channel (right ventricle outflow) and posteromedial aortic channel (left ventricle outflow).
Conducting System:
- Sinoatrial (SA) node develops in the right wall of the sinus venosus near the superior vena cava entrance.
- Atrioventricular (AV) node and bundle of His derive from the left wall of the sinus venosus and the AV canal.

Aortic Arch Derivatives:
- 3rd arch: Forms common carotid artery and proximal internal carotid artery bilaterally.
- 4th arch: Left side forms part of the aortic arch; right side forms proximal right subclavian artery.
- 6th arch (Pulmonary arch): Gives rise to pulmonary arteries; distal left 6th arch persists as the ductus arteriosus.

Aortic Arches Remodeling

Vitelline & Umbilical Arteries:
- Vitelline arteries fuse into celiac (foregut), superior mesenteric (midgut), and inferior mesenteric (hindgut) arteries.
- Umbilical arteries carry blood to the placenta; distal parts obliterate postnatally into median umbilical ligaments.
Venous System:
- Vitelline veins: Form the hepatic portal system.
- Umbilical veins: Right vein regresses; left vein carries oxygenated blood from placenta and shunts through the liver via the ductus venosus.
- Cardinal veins: Drain the body wall, head, neck, and limbs.

Fetal Circulation Shunts:
- Ductus venosus: Directs oxygenated blood from umbilical vein to inferior vena cava.
- Foramen ovale: Shunts high-oxygen blood from right atrium directly into left atrium.
- Ductus arteriosus: Directs desaturated pulmonary trunk blood into descending aorta to supply the lower body.

Fetal and Newborn Circulation

Postnatal Changes:
- Cessation of placental blood flow and expansion of lungs lower right atrial pressure and elevate left atrial pressure.
- Umbilical vein $\rightarrow$ Ligamentum teres (round ligament of liver).
- Ductus venosus $\rightarrow$ Ligamentum venosum.
- Ductus arteriosus $\rightarrow$ Ligamentum arteriosum.
- Umbilical arteries $\rightarrow$ Median umbilical ligaments.
- Foramen ovale $\rightarrow$ Closes against septum secundum to form the fossa ovalis.