Endothelial progenitor cells (EPC) are bone-marrow derived circulating cells
participating in angiogenesis and vascular homeostasis. Reduced numbers
of circulating EPC are observed in patients with various cardiovascular
diseases and are related to an increased risk for future cardiovascular events
and death. Little is known about functional changes. The aim of this thesis
was to study the function of EPC from patients with coronary artery disease
(CAD) or with cardiovascular risk factors such as diabetes or advanced age.
In particular, underlying molecular mechanisms were examined and potential
therapeutic approaches were explored.
CAD patients had reduced EPC numbers, which were correlated with
increased plasma concentration of asymmetric dimethylarginine (ADMA), an
endogenous nitric oxide synthase (NOS) inhibitor. In vitro, ADMA impaired
EPC function which could be restored by statin treatment. In addition, EPC
number and function decreased with age. Treatment of volunteers with
growth hormone increased EPC levels and improved EPC function. Animal
and in vitro studies showed the EPC increase to be directly mediated by the
insulin-like growth factor 1 (IGF-1), which enhanced endothelial NOS
expression of the EPC in a phosphoinositide-3-kinase/Akt dependent
manner. Growth hormone-mediated increase in IGF-1 reversed age-related
EPC dysfunction. Finally, function of EPC from patients with type II diabetes
mellitus was analysed. Uncoupling of eNOS occurred within diabetic EPC
and resulted in enhanced superoxide anion formation with subsequent EPC
dysfunction. EPC dysfunction was protein kinase C-dependent, associated
with reduced intracellular tetrahydrobiopterin (BH4) concentrations and
reversible after exogenous BH4 treatment. Impairment of EPC function is
likely to contribute to the pathogenesis of vascular disease in diabetes
mellitus.
In conclusion, mechanisms underlying EPC dysfunction in various
cardiovascular diseases were investigated and novel treatment approaches
for dysfunctional EPC were explored. The knowledge may provide clues for
the therapy and prevention of certain cardiovascular diseases.