Published Online
on January 19, 2004

A more recent version of this article appeared on February 3, 2004

This Article Full Text (PDF) All Versions of this Article: 109/4/537    most recent 01.CIR.0000109699.45186.30v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ling, S. Articles by Sudhir, K. Search for Related Content PubMed PubMed Citation Articles by Ling, S. Articles by Sudhir, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ESTRADIOL Related Collections Risk Factors

Submitted on July 9, 2003
Revised on September 26, 2003
Accepted on September 26, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: ksudhir{at}cvmed.stanford.edu.

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; 17-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

This article has been cited by other articles:

				H. Okura, Y. Takada, A. Yamabe, T. Kubo, K. Asawa, T. Ozaki, H. Yamagishi, I. Toda, M. Yoshiyama, J. Yoshikawa, et al. Age- and Gender-Specific Changes in the Left Ventricular Relaxation: A Doppler Echocardiographic Study in Healthy Individuals Circ Cardiovasc Imaging, January 1, 2009; 2(1): 41 - 46. [Abstract] [Full Text] [PDF]

				Y. D. Krom, N. M.M. Pires, J. W. Jukema, M. R. de Vries, R. R. Frants, L. M. Havekes, K. W. van Dijk, and P. H.A. Quax Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists Cardiovasc Res, January 1, 2007; 73(1): 217 - 226. [Abstract] [Full Text] [PDF]

				D. J. Handelsman The Rationale for Banning Human Chorionic Gonadotropin and Estrogen Blockers in Sport J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1646 - 1653. [Abstract] [Full Text] [PDF]

				O. W.H. van der Heijden, Y. P.G. Essers, M. E.A. Spaanderman, J. G.R. De Mey, G. J.J.M. van Eys, and L. L.H. Peeters Uterine Artery Remodeling in Pseudopregnancy Is Comparable to That in Early Pregnancy Biol Reprod, December 1, 2005; 73(6): 1289 - 1293. [Abstract] [Full Text] [PDF]

				H.M. O. Farouque, J. A. Tremmel, F. R. Shabari, M. Aggarwal, W. F. Fearon, M. K.C. Ng, M. Rezaee, A. C. Yeung, and D. P. Lee Risk factors for the development of retroperitoneal hematoma after percutaneous coronary intervention in the era of glycoprotein IIb/IIIa inhibitors and vascular closure devices J. Am. Coll. Cardiol., February 1, 2005; 45(3): 363 - 368. [Abstract] [Full Text] [PDF]