Mechanical stimulation of angiogenesis
is not well characterized. There
is a significant amount of controversy with regard to shear stress
acting on capillaries to cause angiogenesis, although current knowledge
suggests that increased muscle contractions may increase angiogenesis.
This may be due to an increase in the production of nitric oxide during
exercise. Nitric oxide results in vasodilation of blood vessels.
Chemical stimulation of angiogenesis is performed by various
angiogenic proteins, including several growth factors.
||Promotes proliferation & differentiation of endothelial
cells, smooth muscle cells, and fibroblasts
|VEGFR and NRP-1
||Integrate survival signals
|Ang1 and Ang2
|PDGF (BB-homodimer) and PDGFR
||recruit smooth muscle cells
|TGF-β, endoglin and TGF-β receptors
||↑extracellular matrix production
|Integrins αVβ3, αVβ5
(?) and α5β1
||Bind matrix macromolecules and proteinases
|VE-cadherin and CD31
||endothelial junctional molecules
||Determine formation of arteries or veins
||remodels extracellular matrix, releases and activates growth
|plasminogen activator inhibitor-1
||stabilizes nearby vessels
|eNOS and COX-2
||regulates angioblast differentiation
||Regulates endothalial transdifferentiation
The fibroblast growth factor (FGF) family with its prototype members
FGF-1 (acidic FGF) and FGF-2 (basic FGF) consists to date of at least
22 known members. Most are 16-18 kDa single chain peptides and display
high affinity to heparin and heparan sulfate. In general, FGFs
stimulate a variety of cellular functions by binding to cell surface
FGF-receptors in the presence of heparin proteoglycans. The
FGF-receptor family is composed of seven members and all the receptor
proteins are single chain receptor tyrosine kinases that become
activated through autophosphorylation induced by a mechanism of FGF
mediated receptor dimerization. Receptor activation gives rise to a
signal transduction cascade that leads to gene activation and diverse
biological responses, including cell differentiation, proliferation,
and matrix dissolution — thus initiating a process of mitogenic
activity critical for the growth of endothelial cells, fibroblasts, and
smooth muscle cells.
FGF-1, unique among all 22 members of the FGF
family, can bind to all seven FGF-receptor subtypes, making it the
broadest acting member of the FGF family, and a potent mitogen for the
diverse cell types needed to mount an angiogenic response in damaged
(hypoxic) tissues, where upregulation of FGF-receptors occurs. FGF-1
stimulates the proliferation and differentiation of all cell types
necessary for building an arterial vessel, including endothelial cells
and smooth muscle cells; this fact ''distinguishes FGF-1 from other
pro-angiogenic growth factors'', such as vascular endothelial growth
factor (VEGF) which primarily drives the formation of new capillaries.
Until now (2007), three human clinical trials have been successfully
completed with FGF-1 in which the angiogenic protein was injected
directly into the damaged heart muscle. Also, one additional human
FGF-1 trial has been completed to promote wound healing in diabetics
with chronic wounds.
Besides FGF-1, one of the most important functions of fibroblast
growth factor-2 (FGF-2 or bFGF) is the promotion of endothelial cell
proliferation and the physical organization of endothelial cells into
tube-like structures, thus promoting angiogenesis. FGF-2 is a more
potent angiogenic factor than VEGF or PDGF (platelet-derived growth
factor), however, less potent than FGF-1. As well as stimulating blood
vessel growth, aFGF (FGF-1) and bFGF (FGF-2) are important players in
wound healing. They stimulate the proliferation of fibroblasts and
endothelial cells that give rise to angiogenesis and developing
granulation tissue, both increase blood supply and fill up a wound
space/cavity early in the wound healing process.
VEGF (Vascular Endothelial Growth Factor) has been demonstrated to
be a major contributor to angiogenesis, increasing the number of
capillaries in a given network. Initial ''in vitro'' studies
demonstrated that bovine capillary endothelial cells will proliferate
and show signs of tube structures upon stimulation by VEGF and bFGF,
although the results were more pronounced with VEGF. Upregulation of
VEGF is a major component of the physiological response to exercise and
its role in angiogenesis is suspected to be a possible treatment in
vascular injuries. In vitro studies clearly demonstrate that VEGF is a
potent stimulator of angiogenesis because in the presence of this
growth factor plated endothelial cells will proliferate and migrate,
eventually forming tube structures resembling capillaries. Ang1 and
Ang2 are protein growth factors which act by binding their receptors,
Tie-1 and Tie-2; while this is somewhat controversial, it seems that
cell signals are transmitted mostly by Tie-2; though some papers show
physiologic signaling via Tie-1 as well. These receptors are tyrosine
kinases. Thus, they can initiate cell signaling when ligand binding
causes a dimerization that initiates phosphorylation on key tyrosines.
Another major contributor to angiogenesis is matrix
metalloproteinase (MMP). MMPs help degrade the proteins that keep the
vessel walls solid. This proteolysis allows the endothelial cells to
escape into the interstitial matrix as seen in sprouting angiogenesis.
Inhibition of MMPs prevents the formation of new capillaries. These
enzymes are highly regulated during the vessel formation process
because destruction of the extracellular matrix would decrease the
integrity of the microvasculature. Dll4 is a transmembrane ligand, for
the Notch family of receptors.
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