Positive effect of treatment with synthetic steroid hormone tibolon on intimal hyperplasia and restenosis after experimental endothelial injury of rabbit carotid artery.
BACKGROUND
Arterial intimal hyperplasia and following restenosis may be inhibited by estrogens. We investigated the effect of a synthetic steroid hormone, Tibolon: (a) on intima hyperplasia and restenosis in vivo, and (b) on production of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), endothelial cell proliferation and apoptosis in vitro.


METHODS
Influence of Tibolon treatment (0.1 mg/kg body weight, during 3 days before and 3 weeks after the operation as a drinking solution once daily) on neointimal formation (measured by morphometry) and arterial wall damage (by qualitative histology) were investigated in vivo using an animal model of balloon injury of carotid artery. In human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC-1), the effect of Tibolon (0.1 microg/ml) on eNOS and VEGF was assessed by ELISA. Cell proliferation was induced by VEGF(165) and measured by BrdU incorporation assay, cell apoptosis was detected colorimetrically measuring DNA fragmentation.


RESULTS
Balloon injury resulted in neointima formation and prominent damage of the carotid artery wall. Treatment with Tibolon increased luminal area, decreased intimal area and intima to media ratio, and promoted better reparation of damaged vessel wall. In vitro, Tibolon treatment did not influence the expression of eNOS protein in HUVEC as well as cell proliferation rate but reduced apoptosis of endothelial cells by about 40%. Additionally, this treatment suppressed basal and IL-1beta-stimulated synthesis of VEGF in HMEC-1.


CONCLUSIONS
Tibolon treatment suppressed neointimal formation and promoted better reparation of damaged vessel wall in carotid artery after balloon injury. This positive effect seems to be associated with improved endothelial cell survival resulting possibly in increased NO production. It might be also related to the decrease of VEGF generation.
Nanobashvili
J
J
Department of Vascular Surgery, University of Vienna, Austria. josif.nanobachvili@akh-wien.ac.at
Prager
M
M
Jozkowicz
A
A
Neumayer
C
C
Fügl
A
A
Blumer
R
R
Cabaj
A
A
Wrba
F
F
Polterauer
P
P
Huk
I
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries; D016893:Carotid Stenosis / Q000503:physiopathology / Q000517:prevention & control*; D002404:Catheterization; D002455:Cell Division / Q000187:drug effects; D006965:Hyperplasia; D008297:Male; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects; D009652:Norpregnenes / Q000494:pharmacology*; D011817:Rabbits; D013256:Steroids / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects
D009652:Norpregnenes; D013256:Steroids; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; C027385:tibolone