Recent Advances in Angiogenesis and ... - Bentham Science

32 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Crivellato and Ribatti
therapy is a novel and effective approach for
inflammatory bowel disease treatment.
The VEGF family of growth factors control
pathological angiogenesis and increased vascular
permeability in important eye diseases such as diabetic
retinopathy and age-related macular degeneration.
Recent findings suggest a role of VEGFR-1 as a
functional receptor for placenta growth factor (PlGF)
and VEGF-A in pericytes and vascular smooth muscle
cells in vivo rather than in endothelial cells [10]. In
addition, VEGFs secreted by epithelia, including the
retinal pigment epithelium, are likely to mediate
paracrine vascular survival signals for adjacent
endothelia. In the choroid, derailment of this paracrine
relation and overexpression of VEGF-A by the retinal
pigment epithelium may explain the pathogenesis of
subretinal neovascularisation in age-related macular
degeneration. On the other hand, this paracrine relation
and other physiological functions of VEGFs may be
endangered by therapeutic VEGF inhibition, as is
currently used in several clinical trials in diabetic
retinopathy and age-related macular degeneration.
In addition to this, the VEGF family of growth factors
appears to stimulate neuroprotection after stroke.
Recent findings from experiments performed on
animals with experimentally evoked focal cerebral
ischemia suggest that the neuroprotective activity of
VEGF runs in parallel with its ability to promote
neurogenesis and angiogenesis and that these effects
may operate independently through multiple
mechanisms [11]. The above-mentioned three major
features characterizing the neurobiological activity of
VEGF, i.e. neuroprotection, neurogenesis, and
angiogenesis, together with their possible functional
link(s), provide the rationale for considering VEGFbased
therapy as a promising future avenue for a more
effective treatment of at least some neurodegenerative
disorders and stroke. Moreover, the possibility of
using neutralizing factors of VEGF or VEGF receptor
antagonists may reveal a way of preventing many
dangerous pathologies, including post-ischemic
disturbances in cardiac and neurological disorders, or
hypervascularization in avascular structures of the eye.
3. NEUTROPHILS
Neutrophils, or polymorphonuclear granulocytes, are
blood cell leukocytes which play a basic role in host
defence and inflammation. During the acute
inflammatory response, neutrophils extravasate from
the circulation into the tissue, where they exert their
defence functions. Increasing evidence supports the
concept that these immune cells also contribute to
inflammation-mediated angiogenesis in different
flogistic conditions. Neutrophils indeed are a source of
soluble mediators which, besides proinflammatory
activity, exert important angiogenic functions. VEGF,
interleukin (IL)-8, tumor necrosis factor (TNF)-,
hepatocyte growth factor (HGF) and matrix
metalloproteinases (MMPs) are the most important
activators of angiogenesis produced by these cells [12-
14]. In this perspective, microarray technique has
recently revealed about thirty angiogenesis-relevant
genes in human polymorphonuclear granulocytes [15].
Interestingly, neutrophil-derived VEGF can stimulate
neutrophil migration [16]. Thus neutrophil
contribution to both normal and pathological
angiogenesis may be sustained by an autocrine
amplification mechanism that allows persistent VEGF
release to occur at sites of neutrophil accumulation.
Production and release of VEGF from neutrophils has
been shown to depend from the granulocyte-colony
stimulating factor (G-CSF) [17]. Evidence for the
possible role of polymorphonuclear granulocytes in
inflammation-mediated angiogenesis and tissue
remodeling was initially provided by the finding that
CXC receptor 2 (CXCR2)-deficient mice, which lacks
neutrophil infiltration in thioglycollate-induced
peritonitis [18], showed delayed angiogenesis and
impaired cutaneous wound healing [19]. More
recently, human polymorphonuclear granulocytes have
demonstrated the ability to directly induce the
sprouting of capillary-like structures in in vitro
angiogenesis assay. This angiogenic capacity appears
to be mediated by secretion of both preformed VEGF
from cell stores and de novo synthesized IL-8 [15].
Angiogenesis is a hallmark of the synovium in chronic
septic arthritis. Analysis of the synovium in patients
with chronic pyogenic arthritis identified dramatic
neovascularization and cell proliferation, accompanied
by persistent bacterial colonization and heterogeneous
inflammatory infiltrates rich in CD15+ neutrophils, as
histopathologic hallmarks [20]. By using a modified
angiogenic model, allowing for a direct analysis of
exogenously added cells and their products in collagen
onplants grafted on the chorioallantoic membrane of
the chicken embryo, it has recently been demonstrated
that intact human neutrophils and their granule
contents are highly angiogenic [21]. Furthermore,
purified neutrophil MMP-9, isolated from the released
granules as a zymogen (proMMP-9), constitutes a
distinctly potent proangiogenic moiety inducing
angiogenesis at subnanogram levels. The angiogenic
response induced by neutrophil proMMP-9 requires
activation of the tissue inhibitor of metalloproteinases
(TIMP)-free zymogen and the catalytic activity of the
activated enzyme.
Neutrophils not only activate but also modulate the
angiogenic process. Neutrophil elastase, a serine
protease released from the azurophil granules of
activated neutrophil, proteolytically cleaves angiogenic
growth factors such as basic-fibroblast growth factor
(FGF)-2 and VEGF [22]. Neutrophil elastase degrades
FGF-2 and VEGF in a time- and concentrationdependent
manner, and these degradations are
suppressed by sivelestat, a synthetic inhibitor of
neutrophil elastase. The FGF-2- or VEGF-mediated
proliferative activity of human umbilical vein