The Angiogenesis Process: How Do New Blood Vessels Grow?
The process of angiogenesis in a healthy adult occurs as an orderly series of events:
- Blood vessels provide nutrients and oxygen throughout the body and are comprised of an inner lining of closely assembled endothelial cells ensheathed by pericytes, (the basement membrane) embedded in the stromal compartment (various stromal cells and extracellular matrix).
- In healthy adults, a balance of growth factor signaling maintains endothelial cells in a quiescent, or resting state.
- To monitor and supply sufficient amounts of oxygen to surrounding tissues, blood vessels have oxygen and hypoxia-induced sensors, or receptors, which allow vessel remodeling to adjust the blood flow accordingly.
- Hypoxia or other endogenous signals activate cells and induce the release signaling factors (such as VEGF, Ang-2, FGF and chemokines) to promote the growth of new blood capillaries from pre-existing vessels – a process called angiogenesis.
- Pericytes detach from the vessel (Ang-2 signaling), and endothelial cells are activated and lose their close contact as the vessel dilates (VE-cadherin signaling).
- In sprout formation, a tip cell is selected (selection influenced by Neuropilin, VEGF/VEGFR and NOTCH / DLL4 and JAGGED1 signaling) which releases matrix metalloproteases (MT1-MMP) to degrade the basement membrane and remodel the extracellular matrix.
- Tip cells are polarized and extend numerous ﬁlopodia to guide sprout migration (via semaphorins, ephrins, and integrins guidance signals) toward angiogenic stimuli (VEGF gradient). Tip cells are primarily migratory and do not proliferate.
- Stalk cells follow the tip cell and proliferate, extending the sprout. Proliferating stalk cells establish junctions with neighboring endothelial cells and release molecules such as EGFL7 (an endothelial cell chemoattractant expressed by proliferating endothelial cells) that bind to extracellular membrane components and regulates vascular lumen formation.
- Fusion of neighboring branches occurs when 2 tip cells encounter each other, establish EC-EC junctions (VE-cadherin, Ang-1) and form a continuous lumen. Extracellular matrix is deposited to establish a new basement membrane (TIMPs), endothelial cell proliferation ceases, and pericytes are recruited to stabilize the new vessel (PDGFR/PDGF-B, Ang-1)
- Once blood flow is established, the perfusion of oxygen and nutrient reduces angiogenic stimuli (VEGF expression) and inactivates endothelial cell oxygen sensors, re-establishing the quiescent state of the blood vessel.
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