Biomedical Engineering Reference
In-Depth Information
development and in wound healing, because
the higher metabolic activities of cells within
developing and healing tissues increase their
nutrient and oxygen requirements [
result, the hematopoietic cells are protected
from myelosuppressive stresses [
9
].
].
Two classes of angiogenic factors and their
receptors are associated with new vessel forma-
tion [
32
2.2.3.1 The VEGF Family and Receptors
The VEGF family of genes is currently known
to comprise fi ve related genes: VEGF A, B, C,
and D and placental growth factor (PlGF). All
of these have some sequence similarity to plate-
let-derived growth factor (PDGF). The VEGF
proteins are roughly
]. These are the vascular endothe-
lial growth factor (VEGF) [
60
,
130
61
] and the
angiopoietin (Ang) [
] families.
VEGFs promote vascular permeability and
stimulate mitogenesis in vascular endothelial
cells. In conjunction with the angiopoietins
(see below), VEGF stimulates endothelial-cell
survival by inhibiting endothelial-cell apopto-
sis. The VEGFs are produced primarily in
response to hypoxia-induced transcription
factors (Hif
98
kDa in size and exist as
homodimers. Some of the VEGF isotypes bind
to heparin. This enhances retention in the ECM
and presentation to cellular receptors. Of the
genomic subtypes, VEGF A is the most preva-
lent, based on tissue distribution and expres-
sion levels. Selective exon splicing leads to
variants of VEGF A, of which six have been
identifi ed. They are denoted as VEGF
45
), which are expressed
by many stromal and extracellular matrix
(ECM)-producing cells in tissues with a high
degree of vascularization. Vascular endothelial
cells express most receptors for the various
VEGF isoforms and are the primary responders
to VEGF.
The angiopoietins, like the VEGFs, are
expressed by stromal, mesenchymal, and
smooth-muscle cells of larger vessels. Their
receptors are expressed primarily on endothe-
lial cells. Angiopoietins appear to be intimately
involved in vessel remodeling and may play a
particular role in wound-healing and tissue-
repair situations where there are pre-existent
vessels [
1
α
and Hif
2
α
121
,
145
,
165
, based on their amino
acid lengths. Of these, VEGF
,
183
,
189
, and
206
appear
to be the most commonly expressed, whereas
the
121
and
165
variants maintain exons
that encode the heparin-binding domains
[
165
,
189
, and
206
].
VEGFs have multiple receptors, including
VEGFR
201
1
, also known as Flt-
1
, VEGFR
2
(KDR
or Flk
). Each of these
receptors is characterized by multiple IgG-like
extracellular domains, and each is coupled to
intracellular signaling networks through an
intracellular domain that has tyrosine kinase
activity. Two other more distantly related mem-
brane receptors, neuropilin
1
), and VEGFR
3
(Flt-
4
is
up-regulated by hypoxia and the associated Hif
1
α
171
,
202
]. The expression of Ang
2
factor, VEGF, angiotensin II, leptin, and
estrogen. Ang
, also inter-
act selectively with various VEGF molecules.
VEGFR
1
and
2
expression is down-regulated
by basic fi broblast growth factor (bFGF). TNF-
α
2
also exists in a soluble form that lacks
the ability for intracellular signaling and
antagonizes the less soluble form of VEGFR
1
expression, with up- or
down-regulation dependent on the tissue type
[
also regulates Ang
2
.
Each of the VEGF receptors differs in its inter-
action with the VEGF isotypes. VEGF A inter-
acts with VEGFR
1
expression, although not extensively
characterized as yet, appears to be up-
regulated in response to hypoxia [
75
]. Ang
1
].
Unlike VEGF, angiopoietins are not mito-
genic but promote cell survival by blocking
apoptotic signals. Ang
167
and both neuropilins,
VEGF B interacts with VEGFR
1
and
2
1
and neuropilin
1
, and VEGF C and D interact with VEGFR
2
also has strong che-
moattractant properties for endothelial cells
and promotes the adhesion of hematopoietic
stem cells. Angiopoietins appear to stimulate
both dissolution and migration of endothelial
cells from pre-existent vessels and, in conjunc-
tion with VEGF promote cell survival and sta-
bilize newly formed vessels in [
1
and
, whereas PlGF only interacts with
VEGFR
3
. These receptors also have the ability
to signal utilizing a variety of intracellular
pathways and can activate PLC, Ras, Shc, Nck
PKC, and PI
1
3
kinase.
98
,
171
]. Recent
2.2.3.2 Angiopoietins and Tie Receptors
Three angiopoietins (Ang
studies have shown Tie
/angiopoietin signal-
ing to regulate the hematopoietic stem-cell qui-
escence niche in the bone marrow niche. As a
2
1
,
2
, and
3
/
4
) have
been identifi ed. They are made up of
498
amino
