Effects of 17beta-estradiol on growth and apoptosis in human vascular endothelial cells: influence of mechanical strain and tumor necrosis factor-alpha.
Vascular endothelial cell (EC) integrity is key to arterial health; endothelial dysfunction is linked to atherogenesis. Atherosclerosis shows a male preponderance, possibly related to the protective effect of estrogens in women. This study examined the effect of estrogens on growth, apoptosis and adhesion molecule expression in cultured human EC. The effects of 17beta-estradiol (E2) were studied in human umbilical vein endothelial cells (HUVEC) under normal culture conditions, and following exposure to cyclic mechanical strain or tumor necrosis factor alpha (TNFalpha). E2 enhanced HUVEC growth in serum-enriched media, in a concentration-dependent manner. This up-regulation of EC growth by E2 was associated with an increase in telomerase activity, assessed by PCR-based TRAP analysis. Cyclic strain enhanced [(3)H]-thymidine incorporation into DNA, and increased activation of mitogen-activated protein (MAP) kinase ERK1/2 and expression of early growth genes (Egr-1 and Sp-1); E2 attenuated the strain-induced ERK1/2 activation but not the early growth gene expression or DNA synthesis. TNFalpha (20 ng/mL) induced apoptosis in HUVEC, causing a decrease in DNA synthesis, increase in floating and Annexin-V-stained cell numbers, and morphological changes. TNFalpha also upregulated ERK1/2 activity and expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin). E2 significantly attenuated the effects of TNFalpha on ERK1/2 activity, apoptosis, and E-selectin expression in the cells. Thus, estradiol enhances growth and reduces TNFalpha-induced apoptosis in EC; enhanced EC growth may be mediated via upregulation of telomerase activity. These effects are possible cellular mechanisms underlying female gender-associated cardiovascular protection.
Ling
Shanhong
S
Monash University Central and Eastern Clinical School, Alfred Hospital, Commercial Road, Melbourne, Vic. 3181, Australia. shanhong.ling@med.monash.edu.au
Zhou
Liemin
L
Li
He
H
Dai
Aozhi
A
Liu
Jun-Ping
JP
Komesaroff
Paul A
PA
Sudhir
Krishnankutty
K
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013314:Stress, Mechanical; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology
D051766:Early Growth Response Protein 1; D011960:Receptors, Estrogen; D016329:Sp1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases; D019098:Telomerase