Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells.
Like most other normal cells, human endothelial cells possess a limited replicative life span, and, after multiple passages in vitro, develop an arrest in cell division referred to as replicative senescence. For many cell types senescence can be delayed by oncogenes or tumor suppressor genes or prevented altogether by malignant transformation; however, once developed, senescence has been regarded as irreversible. We now report that a cytokine, vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), significantly delays senescence in human dermal microvascular endothelial cells (HDMEC). Typically, VPF/VEGF-treated HDMEC could be cultured for at least 15-20 more population doublings (PD) than control cells. Protection from senescence was reversible in that subsequent withdrawal of VPF/VEGF returned cells to the senescent phenotype. Expression of several cell cycle-related genes (p21, p16 and p27) was significantly reduced in VPF/VEGF-treated cells but p53 expression was not significantly altered. Of particular importance, VPF/VEGF was able to rescue senescent HDMEC, restoring them to proliferation, to a more normal morphology, and to reduced expression of a senescence marker, neutral beta-galactosidase. Taken together, VPF/VEGF delayed the onset of senescence and also reversed senescence in microvascular endothelial cells without inducing cell transformation.
Watanabe
Y
Y
Department of Pathology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
Lee
S W
SW
Detmar
M
M
Ajioka
I
I
Dvorak
H F
HF
D019208:Brain-Derived Neurotrophic Factor; D002196:Capillaries / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003864:Depression, Chemical; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D019208:Brain-Derived Neurotrophic Factor; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C019277:brain-derived growth factor