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Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension.
- Source :
-
Cytotherapy [Cytotherapy] 2009; Vol. 11 (4), pp. 492-502. - Publication Year :
- 2009
-
Abstract
- Background Aims: Endothelial apoptosis underlies the pathophysiology of pulmonary arterial hypertension (PAH). Some factors/cytokines released by endothelial progenitor cells (EPC) have been revealed as potent inhibitors of apoptosis. The aim of this study was to investigate the effects of EPC on pulmonary microvascular endothelial cell (PMVEC) survival with the PAH condition.<br />Methods: PMVEC apoptosis was induced by high shear stress (HSS) with serum starvation or pro-inflammatory factors in an artificial capillary system. EPC were delivered into monocrotaline-induced PAH nude rats.<br />Results: PMVEC apoptosis under HSS and serum starvation conditions was significantly inhibited by EPC conditioned medium (CM). It was attenuated by vascular endothelial growth factor (VEGF)-A or -B blocking. EPC CM promoted PMVEC proliferation, which was weakened by VEGF-A or interleukin (IL)-8 blocking. The EPC CM caused less apoptosis of PMVEC induced by HSS plus pro-inflammatory factors. The anti-apoptotic effect of EPC CM was attenuated by blockade of either vascular endothelial growth factor receptor (VEGFR)-1 or -2. However, the pro-proliferating effect appeared to be weakened only by VEGFR-2 blocking. Both Erk1/2 and Akt phosphorylation were enhanced by EPC CM. VEGFR-2 blockage led to significant inhibition of Erk1/2 and Akt activation; VEGFR-1 blockage only of Erk1/2 activation. Human-origin VEGF co-localized with incorporated EPC in small pulmonary arterioles, and EPC transplantation resulted in down-regulation of caspase-3 expression.<br />Conclusions: The VEGF-A/B-VEGFR-1/2-Erk1/2 signal pathway took major responsibility for the anti-apoptotic effects of EPC on PMVEC, and VEGF-A-VEGFR-2-Akt for pro-proliferating effects. Growth factors, secreted in a paracrine manner by transplanted EPC, inhibited cell apoptosis in PAH lung.
- Subjects :
- Adult
Animals
Arterioles enzymology
Arterioles pathology
Caspase 3 metabolism
Cell Proliferation
Culture Media, Conditioned
Cytokines metabolism
Endothelial Cells enzymology
Extracellular Signal-Regulated MAP Kinases metabolism
Hemodynamics
Humans
Hypertension, Pulmonary enzymology
Hypertension, Pulmonary physiopathology
Inflammation metabolism
Lung enzymology
Proto-Oncogene Proteins c-akt metabolism
Rats
Serum
Stress, Mechanical
Vascular Endothelial Growth Factor A metabolism
Vascular Endothelial Growth Factor Receptor-2 metabolism
Apoptosis
Endothelial Cells cytology
Hypertension, Pulmonary pathology
Hypertension, Pulmonary therapy
Microvessels pathology
Stem Cell Transplantation
Stem Cells cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1477-2566
- Volume :
- 11
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cytotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 19526390
- Full Text :
- https://doi.org/10.1080/14653240902960460