Endothelial nitric oxide synthase is essential for circulating angiogenic cell biology and ischemia-directed homing.

摘要

The goal of this thesis was to eludicate the nature of ischemia-directed homing of circulating progenitor cells, with focus on the role of eNOS and the interplay between eNOS and the HIF-1 hypoxia signaling pathway.;Firstly, we investigated the phenotype and biological function of circulating angiogenic cells (CAC), a frequently reported circulating progenitor cell type. We demonstrated that in vitro cultured CACs (CAC iv) carry a genetic signature that closely resembles the transcriptome of regulatory macrophages (M2c subtype). Because their gene signature revealed little to no evidence for endothelial cell differentiation, we postulated that these cells - contrary to current scientific opinions - do not undergo endothelial cell transdifferentiation. Transcriptome analysis further indicated entirely new physiological properties related to reverse cholesterol transport, immunomodulation, energy metabolism and NO bioavailability as important in CACiv biology.;Secondly, using knockout mouse strains, we established that eNOS activity is of key importance for progenitor cell mobilization and homing. After a myocardial infarction, the expression of the hypoxia-induced transcription factor HIF-1 and its downstream genes, was markedly depressed under eNOS deficient conditions. The normal homing signal, which is generated under ischemic conditions by the upregulation of specific chemokines and adhesion molecules, was severely blunted in eNOS deficient conditions. eNOS deficiency also reduced the mobilization of progenitor cells out of the bone marrow.;The above-mentioned results stress the importance of normal eNOS activity in circulating progenitor cell biology, mobilization and homing. Pharmacological targeting of eNOS pathways might be of key importance to restore the mobilization and homing potential of progenitor cells under pathophysiological conditions related to eNOS deficiency.