L-sulforaphane Decreased Contractile Response in Mesenteric Arteries in A Rat Model of Gestational Hypertension

Background: Maternal hypertension is a state of inflammation characterized by oxidative stress. Exposure of pregnant rats to the Toll-like Receptor 9 activator, ODN2395, induces hypertension and upregulates vascular oxidative stress. The transcription factor, Nuclear Factor Erythroid 2 Like 2 (Nrf2), is a regulator of antioxidant response, is overexpressed in placentas from patients with preeclampsia. However, the role of Nrf2 in maternal vascular dysfunction is unknown. Hypothesis: L-sulforaphane, an Nrf2 activator, will have anti-contractile effects on arteries from pregnant rats treated with CpG oligonucleotides (a model of gestational hypertension). Methods: Pregnant Sprague-Dawley rats were treated with synthetic unmethylated CpG oligonucleotides (ODN2395, 100µg/intraperitoneal injection) or saline (Control) on gestational day 14, 16, and 18 (term=21-22 days). Blood pressure was measured before pregnancy and on gestational day 19 using the tail cuff method. The contractile responses of mesenteric resistance arteries to a thromboxane A2 (TxA2) mimetic, U46619, in the presence or absence of Nrf2 activator, L-sulforaphane (L-S, 40 µM), were assessed by wire myography on gestational day 21. Results: Rats treated with ODN2395 had greater systolic blood pressure on gestational day 19 compared to control rats (Control, n=9: 100±4 mmHg vs. ODN2395, n=7: 119±4 mmHg, p=0.007). Three-hour but not one-hour incubation with L-sulforaphane reduced the contractile response to U46619 in mesenteric arteries from both ODN2395 and control rats (Peak contraction as %Max KCl (120mM), Control Veh: 120.5%±4.85; Control L-S: 39.1%±7.16; ODN2395 Veh: 111.1%±4.19; ODN2395 L-S: 42.6%±2.68). Conclusions: Pregnancy is a state of oxidative stress and this may explain the anti-contractile effects of L-sulforaphane in arteries from normal, healthy rats. In preeclampsia, levels of oxidative stress are greater compared to normotensive pregnancies and thus, systemic treatment with L-sulforaphane or other Nrf2 activators may improve poor cardiovascular outcomes in pregnancies with preeclampsia.