Restoring placental growth factor-soluble fms-like tyrosine kinase-1 balance reverses vascular hyper-reactivity and hypertension in pregnancy

Abstract

Preeclampsia (PE) is a pregnancy-related hypertensive disorder (HTN-Preg) with unclear mechanism. An imbalance between antiangiogenic 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 assessed the extent of sFlt-1/PlGF imbalance and vascular dysfunction in a rat model of HTN-Preg produced by reduction of uteroplacental perfusion pressure (RUPP), and tested whether inducing a comparable sFlt-1/PlGF imbalance by infusing sFlt-1 (10 μg·kg(-1)·day(-1)) in day 14 pregnant (Preg) rats cause similar increases in blood pressure (BP) and vascular reactivity. Using these guiding measurements, we then tested whether restoring sFlt-1/PlGF balance by infusing PIGF (20 μg·kg(-1)·day(-1)) in RUPP rats would improve BP and vascular function. On gestational day 19, BP was in Preg+sFlt-1 and RUPP > Preg, and in RUPP+PlGF < RUPP rats. 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, phenylephrine (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 nitric oxide synthase (NOS) inhibitor l-NAME or guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or endothelium-denuded, suggesting changes in endothelial NO-cGMP pathway. In Phe precontracted vessels, ACh-induced relaxation was in Preg+sFlt-1 and RUPP < Preg, and in RUPP+PlGF > RUPP, and was blocked by N(ω)-nitro-l-arginine methyl ester (l-NAME) or ODQ treatment or endothelium removal. Western blots revealed that aortic total endothelial NOS (eNOS) and activated phosphorylated-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 balance toward anti-angiogenic sFlt-1 is associated with decreased vascular relaxation and increased vasoconstriction and BP. Restoring the angiogenic/antiangiogenic balance using PlGF enhances endothelial NO-cGMP vascular relaxation and decreases vasoconstriction and BP in HTN-Preg rats and could offer a new approach in the management of PE.

Keywords: angiogenesis; calcium; endothelium; hypertension; nitric oxide; preeclampsia; vascular smooth muscle.