Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists.
OBJECTIVE
Neointima formation is the underlying mechanism of (in-stent) restenosis. 17beta-Estradiol (E2) is known to inhibit injury-induced neointima formation and post-angioplasty restenosis. Estrogen receptor alpha (ERalpha) has been demonstrated to mediate E2 anti-restenotic properties. However, the role of estrogen receptor beta (ERbeta) is not fully elucidated. In the present study, the specific role of vascular ERalpha and ERbeta in neointima formation is assessed.


RESULTS
Neointima formation was induced by placement of a perivascular cuff around the femoral artery of male C57BL/6J mice. E2-eluting cuffs significantly inhibited cuff-induced neointima formation. To address the specific roles of ERalpha and ERbeta on neointima formation, the ERalpha-selective agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT) and the ERbeta-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) were applied via a drug-eluting cuff. PPT inhibited neointima formation at low but not at high concentrations. Conversely, DPN inhibited neointima formation dose dependently. To demonstrate the specificity of these responses, an ERalpha-selective antagonist, MPP, was also used in combination with E2, PPT, or DPN. While the effect of PPT on neointima formation inhibition was blocked by co-delivery of MPP, E2 and DPN could still inhibit neointima formation.


CONCLUSIONS
Our data suggest that, in addition to ERalpha, specific ERbeta activation inhibits neointima formation in a mouse model of restenosis. These data reveal a yet unidentified protective role of ERbeta on neointima formation.
Krom
Yvonne D
YD
Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Pires
Nuno M M
NM
Jukema
J Wouter
JW
de Vries
Margreet R
MR
Frants
Rune R
RR
Havekes
Louis M
LM
van Dijk
Ko Willems
KW
Quax
Paul H A
PH
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004343:Drug Implants; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000032:analysis / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000032:analysis / Q000378:metabolism; D005263:Femoral Artery; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols; D011422:Propionates / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D004343:Drug Implants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol