Mitochondrial fission differentially regulates uterine artery reactivity across reproductive states in rats

Introduction: Uterine artery blood flow increases markedly during pregnancy to match the metabolic demands of the growing fetus. Uterine artery remodeling and changes in uterine artery (UtA) reactivity are essential to facilitate this pregnancy-associated increase in perfusion. Recent studies have identified mitochondrial fission as a contributor to vascular function. Inhibition of fission suppresses contractile responses in mesenteric arteries and aortas from non-pregnant animals; however, the role of mitochondrial fission in UtA reactivity during pregnancy, a physiological state characterized by substantial mitochondrial adaptations remains largely unknown. The objective of this study was to elucidate the role of mitochondrial fission in UtA reactivity across physiological states associated with pregnancy, namely non-pregnant, mid-gestation, and postpartum. We hypothesized that mitochondrial fission is involved in UtA contractile function and that this involvement is modulated by pregnancy. Methods: Contractile responses to phenylephrine (PE) and potassium chloride (KCl) were assessed in isolated UtA from non-pregnant, pregnant (gestational day (GD) 15; term: 22-23 days), and postpartum (3-4 months post-delivery) Sprague-Dawley rats using wire myography. The role of mitochondrial fission was tested using MDIVI-1, a selective inhibitor of dynamin-related protein 1 (DRP1, 10 μM, 30 min). Results: There was a significant drug (Control vs. MDIVI-1) x reproductive state (non-pregnant, pregnant, postpartum) interaction for PE-induced maximum contractions (F(2, 25) = 4.17, p = 0.028, two-way ANOVA). Tukey’s posthoc test indicated that MDIVI-1 suppressed PE-induced responses in UtA from pregnant (%KClmax, Control (n=7): 122.6 ± 6.7 vs. MDIVI-1, (n=6): 89.2 ± 8.5, p< 0.0001) and postpartum rats (%KClmax, Control (n=5): 120.2 ± 10.3 vs. MDIVI-1, (n=5): 101.8 ± 8.4, p=0.029), but not in UtA from non-pregnant rats (%KClmax, Control (n=4): 120.4 ± 11.0 vs. MDIVI-1, (n=4): 108.1 ± 8.7, p=0.374). In contrast, MDIVI-1 reduced KCl-induced maximum contractions similarly across all reproductive states (Drug effect: F(1, 24) = 198.2, p< 0.0001; Reproductive state effect: F(2, 24) = 5.85, p = 0.0085; Interaction: F(2, 24) = 0.96, p = 0.397). Conclusions: Inhibition of mitochondrial fission suppresses UtA contractile responses prior, during, and after pregnancy. UtA sensitivity to fission inhibition is enhanced during pregnancy and continues postpartum, suggesting a persistent shift in mitochondrial contributions to UtA function. These studies advance our understanding of mitochondrial dynamics in maternal vascular function during healthy and complicated pregnancies and may have implications for long-term maternal vascular health following pregnancy. Funding: LLU Deans Stipend Scholarship, NIH R01HL146562, AHA 24POST1198395 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.