Restoring Anti-angiogenic/Angiogenic Balance Reverses Vascular Hyper-reactivity And Hypertension-in-pregnancy

Preeclampsia(PE)is a pregnancy-related hypertensive disorder(HTN-Preg)with unclear mechanism.An imbalance between anti-angiogenic soluble fms-like tyrosine kinase-1(sFlt-1)and angiogenic placental growth factor(PlGF)has been observed in PE,but the vascular targets and signaling pathways involved are unclear.We tested if inducing sFlt-1/PlGF imbalance by infusing sFlt-1(10 ?g/kg/day)in day-14 pregnant(Preg)rats increases blood pressure(BP)and vascular reactivity;and vice versa,if restoring sFlt-1/PlGF balance by infusing PIGF(20 ?g/kg/day)in a rat model of HTN-Preg produced by reduction of uteroplacental perfusion pressure(RUPP)would improve BP and vascular function.On gestation day 19,BP was in Preg+sFlt-1 and RUPP>Preg and in RUPP+P1GF<RUPP.Plasma sFlt-1/PlGF ratio was increased in Preg+sFlt-1 and RUPP,and was reduced in RUPP+PlGF rats.In isolated endothelium-intact aorta,carotid,mesenteric and renal artery,pheylephrine(Phe)and high KCl-induced contraction was in Preg+sFlt-1 and RUPP>Preg and in RUPP+PlGF<RUPP.The differences in vascular reactivity to Phe and KCl between groups were less apparent in vessels treated with the NOS inhibitor L-NAME or guanylate cyclase inhibitor ODQ or endothelium-denuded vessels,suggesting changes in endothelial NO-cGMP pathway.In Phe precontracted vessels,acetylcholine(ACh)-induced relaxation was in Preg+sFlt-1 and RUPP<Preg and in RUPP+PlGF>RUPP,and was blocked by L-NAME or ODQ treatment or endothelium-removal.Western blots revealed that aortic total eNOS and activated phospho-eNOS were in Preg+sFlt-1 and RUPP<Preg and in RUPP+PlGF>RUPP.ACh-induced vascular nitrate/nitrite production was in Preg+sFlt-1 and RUPP<Preg and in RUPP+PlGF>RUPP.Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different among groups.Thus,a tilt in the angiogenic/anti-angiogenic balance towards anti-angiogenic sFlt-1 is associated with decreased vascular relaxation via NO-cGMP and increased vasoconstriction and BP.Restoring the angiogenic/anti-angiogenic balance using PlGF enhances endothelial NO-cGMP vascular relaxation and decreases vasoconstriction and BP in HTN-Preg rats,and could be a new approach in the management of PE.