SENESCENCE AND OVARIECTOMY INCREASE CONTRACTIONS TO THROMBOXANE A2 IN FEMALE MOUSE AORTA: 1D.06

Abstract

Objective: The present study investigates the effects of ovariectomy on vascular reactivity to U-46619, a stable analog of thromboxane A2 (TXA2) of aorta from senescence-accelerated mice (SAM-P8), a murine model of senescence, and from senescence resistant mice (SAM-R1). Design and Methods: Five month old female SAM-P8 (n = 16) or SAM-R1 (n = 16) were used. Mice were divided in two groups: sham-operated and ovariectomized. Twenty eight days after surgery, mice were sacrificed and vascular rings (4 mm long) from thoracic aorta were mounted for isometric recording of tension in organ bath and concentration response curves for U-46619 (10-9 to 10-6 M) were performed. A segment of thoracic aorta was immediately frozen for protein expression studies. Results: In sham-operated group, TXA2 receptor expression and maximal contraction to U46619 of SAM-P8 aortas were markedly higher than in SAM-R1, suggesting than senescence increases contractile response. Ovariectomy increased contraction to U-46619 in SAM-P8. L-NAME (10-4 M), an inhibitor of nitric oxide (NO) synthase, increased the contractions to U-46619 in SAM-R1 and in SAM-P8 aortas from sham-operated groups but did not change in ovariectomized groups, indicating that estrogens modulate the response to TXA2 through NO pathway. The presence of cyclooxygenase inhibitor indomethacin (10-5 M) decreased the sensitivity to U46619 in aortas from two ovariectomized groups and from sham-operated SAM-P8 group. These results point out that ovariectomy and senescence induce the production of contractile prostaglandins in response to TXA2. Conclusions: The results reveal that senescence enhances expression of TXA2 receptor and contraction to U-46619. Both senescence and ovariectomy change the response to TXA2 by decreasing NO activity and increasing contractile prostaglandins release. These effects were markedly increased in ovariectomized mice with accelerated senescence.