Overview
Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to endothelial cells, which aggregate and form the primitive vascular network called the vascular plexus.
Following vasculogenesis, the vascular plexus or the preexisting blood vessels guide new blood vessel formation through angiogenesis. Angiogenesis occurs by two distinct mechanisms: sprouting angiogenesis and intussusceptive angiogenesis.
- Sprouting angiogenesis:
In sprouting angiogenesis, angiogenic stimuli such as injury or growth spurt induce VEGF secretion from surrounding endothelial cells. VEGF binds VEGFR on these cells and signals them to produce matrix metalloproteases, which helps in basement membrane degradation following the detachment of pericytes from the vessel wall. VEGF and other angiogenic signals also stimulate endothelial cells to differentiate into tip and stalk cells. The tip cells extend filopodial structures resembling blind end tubes called sprouts. Tip cells migrate towards the angiogenic stimulus following the VEGF gradient. The stalk cells behind the angiogenic tip proliferate, elongating the tubular structure. Next, the newly formed blood vessel develops a lumen by one of the two processes: cell hollowing and cord hollowing. In the cell hollowing method, intracellular vacuoles fuse and connect adjacent cells, forming a continuous lumen. In the cord hollowing method, endothelial cells forming the tube change their shape to develop a central tubular lumen towards their extracellular side.
- Intussusceptive angiogenesis:
Intussusceptive angiogenesis involves splitting a vessel into two, also called splitting angiogenesis. It is a faster way of new blood vessel formation. The newly formed vessels join the existing vessels and complete the vascular network. Pericytes and smooth muscles surround the newly formed vessel stabilizing them as blood flows through them.
Procedure
In angiogenesis, new blood vessels are formed from pre-existing ones during growth or in response to a stimulus, such as an injury or inflammation.
Following a stimulus, angiogenesis initiating proteins, such as vascular endothelial growth factors or VEGFs, are released.
VEGF activates surrounding endothelial cells to differentiate into specialized tip cells and release matrix metalloproteases that degrade their basement membrane.
These tip cells signal neighboring endothelial cells to differentiate into stalk cells.
As tip cells migrate along the VEGF concentration gradient, capillaries sprout from the walls of the existing vessel.
At the same time, stalk cells behind the endothelial tip multiply to form the body of the new vessel while their intracellular vacuoles merge into a continuous lumen.
The tip cells finally connect the newly formed vessels with the pre-existing ones to create a closed functional network of blood vessels.