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.
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 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.
