Endogenous estrogen deficiency reduces proliferation and enhances apoptosis-related death in vascular smooth muscle cells: insights from the aromatase-knockout mouse.
BACKGROUND
Altered proliferation and death of vascular smooth muscle cells (VSMCs) are important mechanisms in vascular growth and remodeling. This study examined the effect of endogenous estrogens on VSMC proliferation.


RESULTS
An estrogen-deficient animal model, the aromatase-knockout (ArKO) mouse, was used. Primary cultures of VSMCs were established from aortas of 11-week-old male and female ArKO and wild-type (WT) mice. In ArKO cells, the absence of aromatase cytochrome P450 mRNA expression was demonstrated by reverse transcription-polymerase chain reaction; Western blotting showed normal expression of estrogen receptor protein. Proliferative responses to serum or platelet-derived growth factor-BB were lower in ArKO than WT cells; 17beta-estradiol (E2, 10 nmol/L) enhanced the response to platelet-derived growth factor-BB in ArKO cells but inhibited the response in WT cells. E2 inhibited activity of mitogen-activated protein kinase ERK1/2 in WT but not ArKO cells. Apoptosis-related death caused by tumor necrosis factor-alpha was greater in ArKO than in WT cells; this effect in ArKO was attenuated by E2. Differences in VSMC proliferation between ArKO and WT occurred in both sexes. Morphological studies in aortas derived from male mice at 1 year of age demonstrated that medial smooth muscle area was approximately 10% less in ArKO than WT mice at this age.


CONCLUSIONS
Deficiency of endogenous estrogens reduces proliferation and enhances apoptosis-related death in VSMCs; exogenous E2 corrects these abnormalities.
Ling
Shanhong
S
Baker Medical Research Institute, Melbourne, Victoria, Australia.
Dai
Aozhi
A
Dilley
Rodney J
RJ
Jones
Margaret
M
Simpson
Evan
E
Komesaroff
Paul A
PA
Sudhir
Krishnankutty
K
D000818:Animals; D001011:Aorta / Q000033:anatomy & histology; D017209:Apoptosis; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction
D004967:Estrogens; D011960:Receptors, Estrogen; D004958:Estradiol; D001141:Aromatase