Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists

doi:10.1016/j.cardiores.2006.10.024

Cardiovascular Research 2007 73(1):217-226; doi:10.1016/j.cardiores.2006.10.024

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Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists

Yvonne D. Krom^a^,1, Nuno M.M. Pires^b^,c^,1, J. Wouter Jukema^c^,*, Margreet R. de Vries^b, Rune R. Frants^a, Louis M. Havekes^b^,c^,d, Ko Willems van Dijk^a^,d and Paul H.A. Quax^b^,e

^aDepartment of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
^bTNO-Quality of Life, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands
^cDepartment of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
^dDepartment of General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
^eDepartment of Surgery, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

^* Corresponding author. Department of Cardiology, C5-P, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 71 526 6695; fax: +31 71 526 6886. Email address: j.w.jukema{at}lumc.nl

Objective: Neointima formation is the underlying mechanism of(in-stent) restenosis. 17β-Estradiol (E₂) is known to inhibitinjury-induced neointima formation and post-angioplasty restenosis.Estrogen receptor alpha (ER ${alpha}$ ) has been demonstrated to mediateE₂ anti-restenotic properties. However, the role of estrogenreceptor beta (ERβ) is not fully elucidated. In the presentstudy, the specific role of vascular ER ${alpha}$ and ERβ in neointimaformation is assessed.

Methods and results: Neointima formation was induced by placementof a perivascular cuff around the femoral artery of male C57BL/6Jmice. E₂-eluting cuffs significantly inhibited cuff-inducedneointima formation. To address the specific roles of ER ${alpha}$ andERβ on neointima formation, the ER ${alpha}$ -selective agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol(PPT) and the ERβ-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile(DPN) were applied via a drug-eluting cuff. PPT inhibited neointimaformation at low but not at high concentrations. Conversely,DPN inhibited neointima formation dose dependently. To demonstratethe specificity of these responses, an ER ${alpha}$ -selective antagonist,MPP, was also used in combination with E₂, PPT, or DPN. Whilethe effect of PPT on neointima formation inhibition was blockedby co-delivery of MPP, E₂ and DPN could still inhibit neointimaformation.

Conclusions: Our data suggest that, in addition to ER ${alpha}$ , specificERβ activation inhibits neointima formation in a mousemodel of restenosis. These data reveal a yet unidentified protectiverole of ERβ on neointima formation.

KEYWORDS Estrogens; Hormones; Receptors; Restenosis; Animal model

¹ Both authors contributed equally to this work.

Time for primary review 29 days

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