Growth Factors
Adriana Tajonar
Clinical Group
5.22 J
Outline
Endothelium: function and restenosis
Definition of growth factors and their
importance
FGF
VEGF
Conclusions
Questions
04/08/2003
Endothelial cells (ECs)
Form the linings of the
blood vessels
Capable of suiting local
requirements by
adjusting their number
and arrangement
04/08/2003
Van Belle, et. al., RPI website
Endothelial cells (ECs)
Play crucial part in regulating vessel function
and structure by signaling the surrounding
connective tissue and smooth muscle
Maintain a non-adhesive luminal surface and
contribute to fluidity of the blood
04/08/2003 Van Belle, et. al.
Proliferation of endothelial cells
New ECs are generated by simple
duplication of existing ones
ECs proliferate and migrate to cover exposed
surface to repair damage to blood vessel
(e.g. denuded vessel)
ECs turn over very slowly with cell lifetime
– couple of months (liver and lungs)
– years (brain and muscle)
04/08/2003 B. Alberts, et. al.
Endothelium-derived substances control
Vascular Smooth Muscle Cells (VSMCs)
Relaxing factors:
- Prostacyclin
- Endothelium-derived relaxing factor (EDRF) = Nitric oxide
Contracting factors:
- Vasoconstrictor metabolites of arachidonic acid
- Endothelin-1
Induced by stimuli as angiotensin II, catecholamines, FGFs, or
thrombin
Inhibited by NO and prostacyclin
Van Belle, et. al.
04/08/2003
Growth inhibitory effect on VSMCs
Molecules that stimulate VSMC proliferation
- Endothelin
- PDGF
- Angiotensin
Molecules that inhibit VSMC growth
- Heparin and heparin sulfate glycosaminoglycans
Prevent VSMCs from entering S phase
Protect against thrombus formation
- EDRF-NO
Increases cGMP depresses incorporation of 3H-thymidine in
DNA in VSMCs
Inhibit platelet adhesion
Van Belle, et. al.
04/08/2003
Endothelialization after arterial injury
ECs from areas of intact endothelium enter
replication cycle to restore endothelial continuity
– Limited reendothelialization within one month of balloon
angioplasty
– Extensive reendothelialization between 1 and 5 months
after PTCA
Growth factors for ECs play significant role in
process
Neoendothelium’s function remains abnormal for
weeks after the reendothelialization has been
completed
Van Belle, et. al.
04/08/2003
Definition of Growth Factors (GFs)
Natural chemical messengers
Proteins that can control
– Growth
– Proliferation
– Differentiation
– Survival
– Function of different types of cells
Trigger biochemical cascade
The Cooperative Research Centre for Cellular Growth Factors
04/08/2003
Relevance of GFs
Act as local mediators at very low
concentrations (~10-9 – 10-11 M)
Responses to them are slow (on the order of
hours) but quicker than without GFs
Results in changes in gene expression or
protein activity
B. Alberts, et. al.
04/08/2003
Growth Factors in stents?!
Artery deprived of endothelium after stent
implantation
Restenosis: reparative process involving
division of smooth muscle cells and
production of extracellular matrix
Solution: Reendothelialization
Van Belle, et. al.
04/08/2003
Fibroblast Growth Factor (FGF)
Stimulates both ECs and VSMCs
Synthesized and stored by ECs and VSMCs
Has increased stimulation of ECs of denuded
arteries
Achieves total EC regrowth within 10 weeks
Can lead to functional changes at the endothelial
level
Has an unclear effect on neointimal thickening
Problem: also stimulates VSMCs
Van Belle, et. al.
04/08/2003
Vascular Endothelial Growth Factor
(VEGF)
Promotes angiogenesis
Triggers proliferation of vascular endothelial
cells only
Regulates blood vessel growth to match the
needs of the tissue
Controlled through
– changes in the stability of its mRNA
– rate of transcription
04/08/2003 Van Belle, et. al., B. Alberts
Response of ECs to VEGF
EC proliferation increases in dose dependent
manner
Gene expression observed as early as 36 hours
post-transfection of phVEGF165, and persisting for
two weeks
Near complete reendothelialization by 7 days among
VEGF-transfected arteries
Recovery of normal endothelium-dependent
responses within a week
Diminished neointimal thickening
Decrease in cases of thrombotic occlusion
04/08/2003 Van Belle, et. al.
Artery cross-sections
Effect of local delivery of rhVEGF 165 on intimal hyperplasia. (A)
4 weeks post stent implantation with local delivery of rhVEGF. (B)
Control group (no rhVEGF)
04/08/2003
E. Van Belle et. al.
Chemical pathway:
Reception of signal
04/08/2003 Berg, Stryer et. al.
Chemical pathway:
Signal transduction
04/08/2003
B. Alberts, et. al.
Why is VEGF our “ideal growth
factor”?
It acts on endothelial cells SELECTIVELY
Extremely important potential advantage over
FGF
EC reestablish endothelium
Restenosis avoided!
Can be delivered as a protein or by local
gene transfer of gene encoding (which is the
optimal form? production group)
04/08/2003
Conclusions
Accelerated endothelialization may prevent
thrombus formation and intimal growth at the
site of stent implantation
GF cause accelerated endothelial regrowth,
minimize endothelial dysfunction, and
interfere with intimal growth
VEGF’s selectivity is important advantage
over FGF
04/08/2003
Future work
Which genes are activated by the VEGF
cascade
Search if information is available from the
1998 clinical trial
04/08/2003
References
Van Belle E, Bauters C, Asahara T, Isner JM. Endothelial regrowth after arterial injury: from vascular
repair to therapeutics. Cardiovascular Research 1998; 54-61.
Alberts B., et al. Molecular Biology of the Cell, 4th Edition, 2002, Garland Science; 871-887, 1090-
1091,1279-1282.
Kliche S, Waltenberger J. VEGF Receptor Signaling and Endothelial Function. Life 2001; 61-63.
Van Belle E, Maillard L, Tio FO, Isner JM. Accelerated Endothelialization by Local Delivery of
Recombinant Human Vascular Endothelial Growth Factor Reduces In-Stent Intimal Formation. Biochem
Biophys Res Comm 1997; 311-315
Berg JM, Tymoczko JL, Stryer L, Biochemistry, 5th Edition, 2001, W.H. Freeman and Co.; 415
Van Belle E, Tio FO, Couffinhal T, Maillard L, Passeri J, Isner JM. Time course, impact of local catheter
delivery, feasibility of recombinant protein administration, and response to cytokine expedition. Circulation
1997; 438-448.
Schneider DB, Dichek DA. Intravascular Stent Endothelialization: A goal worth pursuing? Circulation 1997;
308-310.
Hombach B, Waltenberger J, Voisard R, Hoher M. Recurrent stenosis following coronary angioplasty.
Clinical, cell, biological, and molecular aspects. Z Kardiol, 1995; Abstract
Isner JM. Vascular endothelial growth factor: gene therapy and therapeutic angiogenesis. Cardiosource
(www.cardiosource.com)
http://bio.bio.rpi.edu/Parsons/index.html
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