47
Angiogenesis
5
Blood vessels develop and grow by three different basic
mechanisms: vasculogenesis in which vessels form by
concatenation of vascular precursor cells into solid cords
that then lumenize; angiogenesis that is the growth of
new blood vessels from pre-existing ones; and intussus-
ception in which new blood vessels form by the prolif-
eration of endothelial cells (EC) that form a pre-existing
vessel into the vessel lumen, originating two blood ves-
sels that split into two opposite sides
(1)
.
Angiogenesis, the growth of new vessels from pre-exist-
ing ones by sprouting of EC into a previously avascular
tissue, is an essential process both in embryonic develop-
ment and in adulthood
(1,2)
. It is a complex multistep pro-
cess involving extracellular matrix degradation and pro-
liferation, survival, migration and anastomosis of EC
(2)
.
The release of extracellular matrix proteases leads to the
degradation of blood vessels basal membrane, EC change
shape, proliferate, invade stroma and form tubular struc-
tures that coalesce. This requires the coordinated action
of a variety of anti and pro-angiogenic factors and cell-
adhesion molecules in endothelial cells. However, if on
one side it promotes tissue repair, on the other hand if
imbalanced it promotes tissue damage. If not tightly reg-
ulated, the angiogenic process is frequently imbalanced,
and associated with several pathological situations
(1,3)
.
Angiogenic process requires the activation of series of re-
ceptors by numerous ligands including Placental Growth
Factor (PIGF), Fibroblast Growth Factors (FGFs),
Angiopoietin-1 and -2 (Ang-1 and -2), Platelet-derived
Growth Factor (PDGF), Hepatocyte Growth Factor
(HGF), Connective Tissue Growth Factor (CTGF)
and Transforming Growth Factors (TGF-
α
e TGF-
β
),
among many others
(1,3-9)
.
However, there is a consensus that the Vascular Endothe-
lial Growth Factor (VEGF) is the most important angio-
genic factor and represents the crucial rate-limiting step
during angiogenesis
(3,10,11)
.
VEGF-A is the prototype member of a gene family that
also includes placenta growth factor (PlGF), VEGF-B,
VEGF-C, VEGF-D, and the orf-virus-encoded VEGF-
E
(11)
. Alternative exon splicing results in the generation of
four main VEGF isoforms, which have respectively 121,
165, 189, and 206 amino acids after the signal sequence
is cleaved (VEGF121, VEGF165, VEGF189, and
VEGF206). Less frequent splice variants have also been
reported, including VEGF145, VEGF183, VEGF162,
and VEGF165b
(8,11)
.
VEGF mediates its biological functions in endothelium
through binding two highly related receptor tyrosine ki-
nases (RTKs), VEGFR-1 and VEGFR-2. It is generally
agreed that VEGFR-2 is the major mediator of the mi-
togenic, angiogenic and permeability-enhancing effects
of VEGF-A
(3)
. VEGFR-1 binds not only VEGF-A, but
also Placenta Growth Factor (PGF) and fails to mediate
a strong mitogenic signal in endothelial cells. It is now
generally agreed that VEGFR-1 plays a role in modula-
tion of activity of VEGF
(10)
.
The mediators of angiogenic process can be modulated
by some molecules and microenvironmental condi-
tions. VEGF is upregulated by cyclo-oxygenase (COX-
2)
(12)
; inflammation with the hypoxic environment and
the cells involved in inflammatory process, release huge
amounts of factors that exert effects on EC and degrade
the extracellular matrix
(2)
.
Angiogenesis can also be suppressed by inhibitory mol-
ecules, such as interferon-
α
, thrombospondin-1, angio-
statin, endostatin or pigment epithelial-derived factor
(PEDF)
(13-17)
.
1. Definition
Author:
Ângela Carneiro, MD
Faculty of Medicine of University of Porto, Hospital S. João, Porto, Portugal.
2. Angiogenic mediators and
modulation of their expression
