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The ECM as a Spatial Organizer of
Growth Factors
Chris Liu
What happens when growth factors are
secreted/released extracellular?
What is a Morphogen?
1) Long-range signalling molecule
2) Acts directly on cells
(Wolpert, 1969)
Different models of Morphogen Action
a) Morphogen Diffusion
b) Morphogen inhibitor diffusion
c) Cytoneme function
a) Close physical interaction
b) Cytoplasmic diffusion.
Along limb buds, can see morphogen gradients.
These factors may be dependent upon:
morphogen transport
morphogen stability
There is also a lot of regulation of morphogen receptors.
Are there other factors?
Heparin Sulfate Proteoglycan (HSPGs) localize many morphogens.
Some representative HSPGs
These are characterized as “cofactors” for signalling.
Through genetic studies, they modify the phenotypes GFs and GFRs
Heparin synthesis genes have also been implicated.
VEGF exists in different isoforms
heparin binding
VEGF exists in different isoforms
Releases soluble VEGF
Cellular Receptors for VEGF
There appears to be synergy between NRP1 and VEGFR-2
VEGF-A (through KO studies) is essential for :
embryonic blood vessel formation, remodeling, and survival.
embryonic lethal.
The same is true for VEGF-Rs (Flk1 and Flt1)
wtVEGF-/- but VEGF120+/+ have:
normal embryonic vascular development
widespread vessel patterning defect
fewer branch points.
larger luminal diameter. (Carmeliet 1999, Stalmans and Ng 2002)
post-natal angiogenesis defects.
(Shima group)
Reduced vascular branching with KO
Heparin binding reduces vessel complexity
However, this defect is NOT cell proliferation.
Instead, new endothelial cells are incorporated into nascent blood
Vessels (which are subsequently bigger).
Greater VEGF dispersion when there is no heparin binding.
Normally, there is a
Steep concentration
Now, the VEGF
Is more dispersed.
Mice expressing ONLY heparing-binding
VEGF (188) have thinner vessels!!
Too much or too little heparin binding of VEGF is a problem
However, double heterozygotes
compensate for each other and are wt.
Various members of the VEGF/PDGF and bFGF are
alternatively spliced
which regulate proteoglycan and ECM binding.
Ref (Betsholtz, 2001, Eriksson and Alitalo 1999)
Are there other molecules that regulate VEGF/growth factors?
Fibronectin binds VEGF
VEGF and FN induce migration.
VEGF and
FN do not induce
Migration alone
(Wijelath, …Rafii, Sobel, Circ Res)
VEGF/FN mediate alpha5beta/FLK-1 interaction
Anti-a5b1 inhibits migration
FN contains 2 VEGF binding sites
FN can be proteolyzed into fragments
VEGF binds mainly FN
Only the N- and C-terminal (not RGD) fragments bind VEGF
Model of VEGF/FN/Flk-1/a5b1 action
Complex induces downstream signalling.
Any thoughts?
How important is this microenvironment?
(Not at cellular level, not at organismal level, but somewhere
in between)
How important is release?
MMPs reveal cryptic binding sites.
Proteases may release bioavailability.