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(Circulation. 2004;109:537-543.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Endogenous Estrogen Deficiency Reduces Proliferation and Enhances Apoptosis-Related Death in Vascular Smooth Muscle Cells

Insights From the Aromatase-Knockout Mouse

Shanhong Ling, MD; Aozhi Dai, MD; Rodney J. Dilley, PhD; Margaret Jones, PhD; Evan Simpson, PhD; Paul A. Komesaroff, MD, PhD^*; Krishnankutty Sudhir, MD, PhD^*

From Baker Medical Research Institute, Melbourne (S.L., A.D., R.J.D., P.A.K., K.S.), and Prince Henry’s Institute for Medical Research, Clayton (M.J., E.S.), Victoria, Australia.

Correspondence to Krishnankutty Sudhir, MD, PhD, Consulting Associate Professor of Medicine, Stanford University, H3554, 300 Pasteur Dr, Stanford, CA 94305. E-mail ksudhir{at}cvmed.stanford.edu

Received July 9, 2003; revision received September 26, 2003; accepted September 26, 2003.

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.

Methods and 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; 17ß-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- 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 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.

Key Words: apoptosis • hormones • muscle, smooth • proliferation

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