Recent Advances in Angiogenesis and ... - Bentham Science

Cross-Link Between Inflammation and Angiogenesis Recent Advances in Angiogenesis and Antiangiogenesis, 2009 31
angiogenesis concomitant with physiological
processes, such as ovulation and endometrial
vascularization during the reconstructive phase of the
menstrual cycle and in pregnancy.
2. VASCULAR ENDOTHELIAL GROWTH
FACTOR AND INFLAMMATORY
ANGIOGENESIS
Vascular endothelial growth factor (VEGF) is a
secreted mitogen highly specific for endothelial cells.
In vivo VEGF induces microvascular permeability and
plays a central role in both angiogenesis and
vasculogenesis [5]. Through alternative mRNA
splicing, a single gene gives rise to several distinct
isoforms of VEGF, which differ in their expression
patterns as well as their biochemical and biological
properties. Two VEGF receptor tyrosine kinases
(VEGFRs) have been identified, VEGFR-1 (Flt-1) and
VEGFR-2 (KDR/Flk-1). VEGFR-2 seems to mediate
almost all observed endothelial cell responses to
VEGF, whereas roles for VEGFR-1 are more elusive.
VEGFR-1 might act predominantly as a ligandbinding
molecule, sequestering VEGF from VEGFR-2
signaling. Several isoform-specific VEGF receptors
exist that modulate VEGF activity. Neuropilin-1 acts
as a co-receptor for VEGF(165), enhancing its binding
to VEGFR-2 and its bioactivity. Heparan sulphate
proteoglycans (HSPGs), as well as binding certain
VEGF isoforms, interact with both VEGFR-1 and
VEGFR-2. HSPGs have a wide variety of functions,
such as the ability to partially restore lost function to
damaged VEGF(165) and thereby prolonging its
biological activity.
Increasing evidence suggests that VEGF-A is one of
the major proangiogenic molecules involved in both
normal and pathologic angiogenesis. The expression
of VEGF-A and its receptor VEGFR-2 is elevated in
patients with inflammatory skin diseases that are
associated with enhanced vascularity such as psoriasis.
Recently, transgenic mice expressing VEGF have been
described to develop a psoriasis-like inflammation
characterized by increased angiogenesis, acanthosis,
and immune cell infiltration [6].
Similarly in human and experimental rheumatoid
arthritis, the VEGF-A pathway is strongly
overexpressed and activated, and its blockade is
clinically beneficial. Indeed, the vasculature plays a
crucial role in inflammation, angiogenesis, and
atherosclerosis associated with the pathogenesis of
inflammatory rheumatic diseases [7]. The endothelium
lining the blood vessels becomes activated during the
inflammatory process, resulting in the production of
several mediators, the expression of endothelial
adhesion molecules, and increased vascular
permeability (leakage). All of this enables the
extravasation of inflammatory cells into the interstitial
matrix. The endothelial adhesion and transendothelial
migration of leukocytes is a well-regulated sequence of
events that involves many adhesion molecules and
chemokines. Primarily selectins, integrins, and
members of the immunoglobulin family of adhesion
receptors are involved in leukocyte 'tethering',
'rolling', activation, and transmigration. There is a
perpetuation of angiogenesis, the formation of new
capillaries from pre-existing vessels, as well as that of
vasculogenesis, the generation of new blood vessels in
arthritis and connective tissue diseases. Several
soluble and cell-bound angiogenic mediators produced
mainly by monocytes/macrophages and endothelial
cells stimulate neovascularization. On the other hand,
endogenous angiogenesis inhibitors and exogenously
administered angiostatic compounds may
downregulate the process of capillary formation. Thus,
the formation of new vessels appears to be an early and
fundamental process for the evolution of the
inflammatory response in synovial joints affected by
arthritis. The propagation of new vessels in the
synovial membrane allows the invasion of this tissue
over the intraarticular cartilage in an adherent fashion.
This process appears to support the active infiltration
of synovial membrane into cartilage and results in
erosion and destruction of the cartilage. This process
results in joint damage and ultimately in deformity, as
the normal joint architecture and balance of tendons
becomes disrupted.
Activation of the VEGF-A pathway has been
demonstrated also in the actively inflamed mucosa of
patients with inflammatory bowel disease. Expression
of both VEGF-A and its receptor VEGFR-2 are
enhanced in tissue biopsy specimens from inflamed
bowel segments. Interestingly, besides its classical
angiogenic activity, VEGF-A can exert
proinflammatory effects on intestinal endothelium,
both in vitro and in vivo. Indeed, recent evidence
shows that angiogenesis is crucial during
inflammatory bowel disease and in experimental
models of colitis [8]. Examination of the relationship
between angiogenesis and inflammation in
experimental colitis shows that initiating factors for
these responses simultaneously increase as disease
progresses and correlate in magnitude. Recent studies
show that inhibition of the inflammatory response
attenuates angiogenesis to a similar degree and,
importantly, that inhibition of angiogenesis does the
same to inflammation. Recent data provide evidence
that differential regulation of the angiogenic mediators
involved in inflammatory bowel disease-associated
chronic inflammation is the root of this pathological
angiogenesis [9]. Many factors are involved in this
phenomenon, including growth factors/cytokines,
chemokines, adhesion molecules, integrins, matrixassociated
molecules, and signaling targets. These
factors are produced by various vascular, inflammatory,
and immune cell types that are involved in
inflammatory bowel disease pathology. Moreover,
recent studies provide evidence that antiangiogenic