Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway.
BACKGROUND
Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis.


METHODS
Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (microCT) and molecular analysis of the vascular tissue.


RESULTS
Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees , P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study.


CONCLUSIONS
In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.
Choi
B G
BG
Mount Sinai School of Medicine, New York, USA.
Vilahur
G
G
Cardoso
L
L
Fritton
J C
JC
Ibanez
B
B
Zafar
M U
MU
Yadegar
D
D
Speidl
W S
WS
Schaffler
M B
MB
Fuster
V
V
Badimon
J J
JJ
D000818:Animals; D001018:Aortic Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002114:Calcinosis / Q000209:etiology* / Q000473:pathology; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D010052:Ovariectomy / Q000009:adverse effects*; D053245:RANK Ligand / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction
D053245:RANK Ligand