Development Of The Vascular System

Question 1

What is vasculogenesis?

Answer 1

De novo formation of blood vessels from endothelial precursors (angioblasts - migrating mesoderm cells).
Hemangioblasts (precursor for blood + endothelial) aggregate to form haematic cords.
Via endoderm signals to extraembryonic mesoderm.

Question 2

How does the dorsal aorta form (example of vasculogenesis)?

Answer 2

Endoderm induces angioblasts in splanchnic mesoderm.
Shh from notochord induces VEGF in somites.
Angioblasts migrate towards VEGF signal.
Hence VEFG + Shh induces tube formation.

Question 3

How is the identity of an artery or vein established?

Answer 3

Shh –> Notch –> Hes (TF) –> Artery –> EphrinB4 ligand (Artery phenotype).
Low/absent Shh –> vein –> EphB2 receptor, repulsed by EphrinB4 (Vein phenotype).

Can also be mediated by blood flow, shear stress.

Question 4

What is angiogenesis?

Answer 4

Formation of new blood vessels from pre-existing ones.
2 types:
- Intussiception: splitting of blood vessels.
- Sprouting angiogenesis.

Question 5

What brings about retinal angiogenesis?

Answer 5

Hypoxia –> HIF1a –> VEGF secretion.

Example of sprouting angiogenesis - BVs will grow out from fovea.

Question 6

How do angiogenic tip cells function?

Answer 6

Sense their environment by sending out filopodia to sense for VEGF.
Repulsive signals guide intersegmental vessel (ISV) growth, along somite boundaries.
Somites express Semaphorin 3a & angiogenic tip cells express PlexinD1 (Semaphorin receptor).

Question 7

What happens when there is loss of Notch signalling?

Answer 7

Causes ectopic tip-cell formation since there’s no lateral inhibition.

E.g. DAPT (gamma-secretase inhibitor) blocks Notch cleavage.

Question 8

What is stabilisation?

Answer 8

1. Functional endothelia change their phenotype, from simple tube to functional vessel, accessory cells.
   Immature endothelium:
   - leaky, compliant, unstable, likely to sprout due to VEGFR1 expression. Blood flow causes cell-ECM stress activating FAK.
   Mature endothelium:
   - tight, elastic, stable, unlikely to sprout due to VEGFR2 expression. Blood flow causes cell-cell stress activating VE-cadherin.
2. Functional endothelia recruit mural cells (capillaries - pericytes & arteries/veins - VSMC).

Question 9

What brings about remodelling?

Answer 9

1. Dependent on function/environment. E.g. Competition for GFs, blood flow can lead to pruning.
2. Closure of ductus arteriosus at birth. Provides O2 to developing lungs & maintained by prostaglandin signalling.

Question 10

What does failure in stabilisation cause?

Answer 10

1. Hereditary haemorrhagic telangiectasia.

2. Mutants in Notch pathway.

Question 11

What is patent ductus arteriosus?

Answer 11

Abnormalities of great vessels, causing large differences between aortic and pulmonary pressures. This prevents normal closure.

Treatment: prostaglandin inhibitors. Fails to close, the surgical closure with clip.

Question 12

What is coarctation of aorta?

Answer 12

Constriction of aorta, obstructs blood flow to rest of body. Found mostly in males.

Question 13

What is a double aortic arch?

Answer 13

Trachea/oesophagus encircled by bilateral aortic arches.