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effects, but generally regarded in negative connotations (chemerin), to show, that
investigation is not finished yet and still exist a lot of controversies and that the
results sometimes seems quite contradictory.
- Vascular endothelial growth factor (VEGF): it is a key and main molecule and
it is present in many pathways responsible for neoangiogenesis. The VEGF
family comprises in mammals five members: VEGF-A, placenta growth factor
(PGF), VEGF-B, VEGF-C and VEGF-D [ 33 ]. The latter ones were discovered
later than VEGF-A, and, before their discovery, VEGF-A was called just
VEGF. A number of VEGF-related proteins encoded by viruses (VEGF-E) and
in the venom of some snakes (VEGF-F) have also been discovered. There is
evidence based on rat model that exercise training improves aging-induced
downregulation of cardiac VEGF angiogenic signaling cascade, thereby contrib-
uting to the exercise-induced improvement of angiogenesis [ 34 ]. On other hand,
a certain degree of restraint is appropriate as another result showed no increased
VEGF synthesis after exercise in heart [ 35 ]. There are many triggers which can
increase the concentration of VEGF that can be produced by several cell types
that stimulates angiogenesis. One of the chemical triggers is prostaglandin E1
[PGE(1)]; cardiac myocytes could be a cellular source of PGE(1)-induced VEGF
expression [ 36 ]. Other trigger can be rise of testosterone levels mediated by exer-
cise. Model of diabetic rat proved that testosterone and exercise can promote
neoangiogenesis. The proangiogenesis effect of testosterone and exercise is
associated with the enhanced expression of VEGF-A and SDF-1a (stromal
cell- derived factor 1) in heart tissue [ 37 ]. VEGF-A can act on several
receptors – Neuropilin1 (NRP1) is important for coronary neoangiogenesis, it is
transmembrane glycoprotein that serves as a receptor for the VEGF 165 isoform
[ 38 ]. Biochemical evidence supports a hypothesis of NRP1 function in which
VEGF binding induces complex formation between NRP1 and tyrosine kinase
receptor VEGF receptor 2 (VEGFR2) to mediate signal transduction of endothe-
lial VEGF signaling [ 38 – 40 ]. VEGF-induced activation of VEGFR2 stimulates
endothelial cell proliferation, migration, and differentiation in most cell cultures
[ 41 ]. From different point of view, VEGF is involved in many pathological con-
ditions as a tumorigenesis and/or atherosclerosis. Bailey with the colleagues
demonstrated that after specified exercise, circulating soluble vascular endothe-
lial growth factor receptor-1 (sFlt-1) (an endogenous VEGF inhibitor) is signifi-
cantly increased in healthy volunteers, which is functionally associated with a
transient decrease in circulating free VEGF [ 42 ]. From this example is clear that
pleiotropic effects of VEGF must be perceived comprehensively and critically.
Exercise affects condition of the heart in a positive way, but pathways behind are
far more complex as we originally thought.- Fibroblast growth factor: In humans, 22 members of the FGF family have been
identified [ 43 ] and from these, mainly FGF2, event. FGF1 has neoangiogenic
potential. They promote angiogenesis by physical organization of endothelial
cells into tube-like structures. Thus, activity of FGFs is stem cells-independent.
These multipotent FGFs are true pluripotent or promiscuous growth factors [ 44 ].M. Miko and I. Varga