KBH3
The development of blood vessels in embryogenesis and tissue repair
Mesodermal
precursor
Vessel repair
VEGFR-1 and -2
PlGF, VEGF-A
Mesoderm induction
Mature vascular system
Maturation, remodelling
‘Hemangioblast’
Hemangioblast’
VEGFRVEGFR-2+
Haematopoiesis
Haematopoietic
stem cell
VEGFRVEGFR-2+
Scl/tal+
TGFβR
PDGFβR
Pruning, remodelling
Vasculogenesis
Angioblast
VEGFRVEGFR-2+
Scl/tal-
VEGFR-1
VEGFR-2
Tie-1
Tie-2
RasGAP
Sprouting and
non-sprouting
angiogenesis
VEGFR-1
VEGFR-2
Tie-1
Tie-2
TGFβR
Vasculogenesis
Primary capillary
plexus
Formation of a functional circulation from endothelial progenitors
KBH1
1
Slide 1
KBH3 Risau, Nature 386, 671(1997)
Kurt Ballmer-Hofer; 13.10.2004
Slide 2
KBH1 a, Vascular progenitors appear in response to basic fibroblast growth
factor(bFGF) and bone morphogenetic protein 4 (BMP4) in the posterior
primitive streak (PPS) as vascular endothelial growth receptor-2
(VEGFR-2)/Flk1-positive mesodermal cells. b, Flk1-positive cells in the
primitive streak give rise to both blood and endothelium
haemangioblasts), but are restricted to haematopoietic or angiogenic fate
after emigrating into extra-embryonic sites (extra-embryonic ectoderm
(EXE), yolk sac and allantois) and intraembryonic sites (embryonic
ectoderm (EEC)). c, In the yolk sac, these progenitors aggregate into
endothelial-lined blood islands that then fuse to generate a primary
capillary plexus (see main text). d, The primary capillary plexus undergoes
remodelling along with intra-embryonic vessels to form a mature
circulation (g). e, Intra-embryonic angioblasts migrate along distinct
pathways before (f) aggregating directly into the dorsal aorta or cardinal
vein, without a plexus intermediate. g, The primary vessels (capillary
plexus, dorsal aorta and cardinal vein) then remodel, together with the
xtraembryonicplexus, to form a mature vasculature, which along with
VEGF and Notch involves the angiopoietins and Tie receptors4. h, Mural
cells (pericytesand smooth-muscle cells) proliferate and differentiate in
response to transforming growth factor- (TGF- ) signalling, and are
recruited to vessels by
platelet-derived growth factor (PDGF) secreted by endothelial cells5,6.
Ang, angiopoietin; Eph, Eph receptor family; Shh, sonic hedgehog; Np,
neuropilin.
Coultas et al. Nature 438 937 (2005)
K. Ballmer-Hofer; 30.03.2006
The development of blood vessels: vasculogenesis versus angiogenesis
Peptide Hormones Involved in Vasculogenesis and Angiogenesis
In embryonic development
Vasculogenesis
Ligand
Receptor
Mature Vessels
VEGF
VEGFR-2
(Flk-1/KDR)
Development
of angioblasts
Ang1
VEGFR-1
(Flt1)
Tie2
Basal membrane
In an adult organism
Angiogenesis
Ang2
Regression
VEGF
AntiVEGF
Tie2 VEGFR-1/2 Therapie
Ang2
Tie2
Pericytes
Interaction with
Destabilization of
Lack of matrix and
pericytes, maintenance
matrix-cell and
survival factors, cell
of vessel integrity cell-cell interactions, death via apoptosis
Interaction between
angiogenesis
endothelial cells
Adapted from D. Hanahan, Science 277, 48 (1977)
KBH2
Artery and vein formation are genetically determined
¾ In arteries VEGFR-2/NRP-1 signaling leads to
ERK1/2 activation
•
•
this is followed by notch signaling
and EphrinB2 expression
¾ In veins signaling by COUP TFII, a transcription
factor, blocks NRP-1 expression resulting in altered
VEGFR-2 signaling
•
•
PI 3-kinase activation which blocks ERK1/2
and Eph B4 expression
2
Slide 4
KBH2 A model for the genetic specification of arterial and venous fates in the
major vessels of the trunk incorporating experimental data from mouse
and zebrafish. Shh expressed in the notochord and floor plate induces
VEGF expression in the somites, which in turn activates the receptor
VEGFR2, expressed on endothelial cells. Activation of the PLC-–MAPK
cascade downstream of VEGFR2 results in activation of ERK and of the
Notch pathway. Foxc1 and Foxc2 promote expression of Notch1 and Dll4,
leading to expression of ephrinB2 and an arterial fate. The interaction
between activated ERK and Foxc1 and Foxc2 has not been elucidated, as
indicated by a dashed line. Conversely, activation of the PI3K pathway
results in activation of Akt and inhibition of ERK, which promotes venous
fate, while repressing arterial fate. Small chemical inhibitors that block
either the PLC-–MAPK or PI3K pathways, such as SL327, GS4898, and
wortmannin, can influence the promotion of cell fate as indicated. Within a
venous cell, the presence of COUP-TFII inhibits neuropilin1 expression,
thus reducing VEGFR2 signaling and Notch activation. As a result, EphB4
is expressed and ephrinB2 is not. Because EphB4 is still present at
reduced levels in venous cells of COUP-TFII null embryos, its expression
must be partially controlled by an unknown pathway.
R. E. Lamont et al., Sci. STKE 2006, pe39 (2006)
K. Ballmer-Hofer; 19.06.2007
Formation of a capillary network
Some cellular factors regulating angiogenesis
Pro-angiogenmic factors
General factors
VEGF, Vascular endothelial growth factor
bFGF, basic fibroblast growth factor
PlGF, Placenta growth factor
PDGF, Platelet-derived growth factor
TGFα, Estrogens, EPO
EGF, IGF 1, IL-3, IL-8
Angiopoietins 1,2
Angiogenin
HIV-1 Tat protein, RGD-peptide
Tumor Necrosis Factor α (TNFα)
...
Anti-Angiogenic factors
Tissue specific factors
EG-VEGF, endocrine gland derived VEGF
...
Tissue specific factors
Pigment epithelium derived factor, PEDF
...
General factors
Thrombospondin (ECM-Protein)
Endostatin (collagen XVIII fragment)
Angiostatin (plasminogen kringle-domain)
Antibodies against VEGF/VEGFR or Integrins
Soluble VEGFR, ‚VEGF trap‘ (sFlt, Ig domain)
Inhibitors of VEGFR kinase, e.g. SU5416
Interferonα
TNFα
PEX, a noncatalytic fragment of MMP-2
Kininostatin, a kinin fragment Bradykinin
...
3
Regulators of angiogenesis
¾ VEGFs and angiopoietins acting on endothelial cells;
¾ Cytokines, chemokines and angiogenic enzymes activating various cell types such as EC or
SMCs;
¾ Indirectly acting factors released by other cell types such as macrophages, platelets,
tumor cells, endothelial cells.
Morphology of endothelial cells
Resting endothelial cell layer
Angiogenic endothelial cell layer
4
Overexpression of angiopoietin 1 promotes excessive vessel growth
KB3
Hemostasis leads to the formation of fibrinclots and a thrombus by platelets
Platelets
Fibrin
Fibrin attracts endothelial cells
coagulation factors stimulate
sprouting of blood vessels via HIF-1
und VEGF
5
Slide 9
KB3
Suri,C. et al., Science 282:468
Kurt Ballmer-Hofer; 01.11.2004
A juvenile hemangioma with many capillaries
From: Tumour angiogenesis, R. Bicknell et al. eds., 1997
Infiltrating ductal breast carcinoma
Prognosis good
Prognosis poor
From: Tumour angiogenesis, R. Bicknell et al. eds., 1997
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