Role of oxidative stress in multiparity-induced endothelial dysfunction

Multiparity is associated with increased risk of cardiovascular disease. We tested whether multiparity induces oxidative stress in rat vascular tissue. Coronary arteries and thoracic aorta were isolated from multiparous and age-matched virgin rats. Relaxation to ACh and sodium nitroprusside (SNP) was measured by wire myography. We also tested the effect of the superoxide dismutase mimetic MnTE2PyP (30 μM), the NADPH oxidase inhibitor apocynin (10 μM), and the peroxynitrite scavenger FeTPPs (10 μM) on ACh-mediated relaxation in coronary arteries. Vascular superoxide anion was measured using the luminol derivative L-012 and nitric oxide (NO) generation by the Griess reaction. Multiparity reduced maximal response and sensitivity to ACh in coronary arteries [maximal relaxation (E_max): multiparous 49 ± 3% vs. virgins 95% ± 3%; EC₅₀: multiparous 135 ± 1 nM vs. virgins 60 ± 1 nM], and in aortic rings (E_max: multiparous 38 ± 3% vs. virgins 79 ± 4%; EC₅₀: multiparous 160 ± 2 nM vs. virgins 90 ± 3 nM). Coronary arteries from the two groups relaxed similarly to SNP. Superoxide anions formation was significantly higher in both coronary arteries (2.8-fold increase) and aorta (4.1-fold increase) from multiparous rats compared with virgins. In multiparous rats, incubation with MnTE2PyP, apocynin, and FeTPPs improved maximal relaxation to ACh (MnTE2PyP: 74 ± 5%; vehicle: 41 ± 5%; apocynin: 73 ± 3% vs. vehicle: 41 ± 3%; FeTPPs: 72 ± 3% vs. vehicle: 46 ± 3%) and increased sensitivity (EC₅₀: MnTE2PyP: 61 ± 0.5 nM vs. vehicle: 91 ± 1 nM; apocynin: 45 ± 3 nM vs. vehicle: 91 ± 6 nM; FeTPP: 131 ± 2 nM vs. vehicle: 185 ± 1 nM). Multiparity also reduced total nitrate/nitrite levels (multiparous: 2.5 ± 2 μmol/mg protein vs. virgins: 7 ± 1 μmol/mg protein) and endothelial nitric oxide synthase protein levels (multiparous: 0.53 ± 0.1 protein/actin vs. virgins: 1.0 ± 0.14 protein/actin). These data suggest that multiparity induces endothelial dysfunction through decreased NO bioavailability and increased reactive oxygen species formation.