Physiological and pathological
all tissues develop a vascular network that provides cells with nutrients and oxygen and
enables them to eliminate metabolic wastes. Once formed, the vascular network is a stable
system that regenerates slowly.
In physiological conditions, angiogenesis occurs primarily in embryo development, during
wound healing and in response to ovulation.
However, pathological angiogenesis, or the abnormal rapid proliferation of blood vessels,
is implicated in over 20 diseases, including cancer, psoriasis and age-related macular
The angiogenic sequence
angiogenic process, as currently understood, can be summarized as follows:
- A cell activated by a lack of oxygen releases angiogenic molecules that attract
inflammatory and endothelial cells and promote their proliferation.
- During their migration, inflammatory cells also secrete molecules that intensify the
- The endothelial cells that form the blood vessels respond to the angiogenic call by
differentiating and by secreting matrix metalloproteases (MMP), which digest the
blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic
- Several protein fragments produced by the digestion of the blood-vessel walls intensify
the proliferative and migratory activity of endothelial cells, which then form a capillary
tube by altering the arrangement of their adherence-membrane proteins.
- Finally, through the process of anastomosis, the capillaries emanating from the
arterioles and the venules will join, thus resulting in a continuous blood flow.
normal regulation of angiogenesis is governed by a fine balance between factors that
induce the formation of blood vessels and those that halt or inhibit the process. When
this balance is destroyed, it usually results in pathological angiogenesis which causes
increased blood-vessel formation in diseases that depend on angiogenesis.
More than 20 endogenous positive regulators of angiogenesis have been described, including
growth factors, matrix metalloproteinases, cytokines, and integrins. Growth factors, such
as vascular endothelial growth factor (VEGF), transforming growth factors (TGF-beta),
fibroblast growth factors (FGF), epidermal growth factor (EGF), angiogenin, can induce the
division of cultured endothelial cells thus indicating a direct action on these cells.
However, other factors have virtually no effect on the division of cultured endothelial
cells or, in the case of TGF-beta and TNF-alpha, paradoxically inhibit their growth
indicating that their angiogenic action is indirect.