Abstract
Adequate perfusion of the placental vasculature is essential to meet the metabolic demands of fetal growth and development. Lacking neural control, local tissue metabolites, circulating and physical factors contribute significantly to blood flow regulation. Nitric oxide (NO) is a key regulator of fetoplacental vascular tone. Nitrite, previously considered an inert end-product of NO oxidation, has been shown to provide an important source of NO. Reduction of nitrite to NO may be particularly relevant in tissue when the oxygen-dependent NO synthase (NOS) activity is compromised, e.g. in hypoxia. The contribution of this pathway in the placenta is currently unknown. We hypothesised that nitrite vasodilates human placental blood vessels, with enhanced efficacy under hypoxia.Placentas were collected from uncomplicated pregnancies and the vasorelaxant effect of nitrite (10−6–5x10−3 M) was assessed using wire myography on isolated pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) under normoxic (pO2 ∼5%) and hypoxic (pO2 ∼1%) conditions. The dependency on the NO–sGC–cGMP pathway and known nitrite reductase (NiR) activities was also investigated. Nitrite caused concentration-dependent vasorelaxation in both arteries and veins, and this effect was enhanced by hypoxia, significantly in CPVs (P < 0.01) and with a trend in CPAs (P = 0.054). Pre-incubation with NO scavengers (cPTIO and oxyhemoglobin) attenuated (P < 0.01 and P < 0.0001, respectively), and the sGC inhibitor ODQ completely abolished nitrite-mediated vasorelaxation, confirming the involvement of NO and sGC. Inhibition of potential NiR enzymes xanthine oxidoreductase, mitochondrial aldehyde dehydrogenase and mitochondrial bc1 complex did not attenuate vasorelaxation. This data suggests that nitrite may provide an important reservoir of NO bioactivity within the placenta to enhance blood flow when fetoplacental oxygenation is impaired, as occurring in pregnancy diseases such as pre-eclampsia and fetal growth restriction.
Highlights
Nitric oxide (NO) is a potent endogenous vasodilator important in the regulation of vasomotor tone, blood flow and systemic blood pressure [1]
The present study shows that 1) inorganic nitrite causes significant vasorelaxation in human chorionic plate vessels; 2) vasorelaxation is enhanced under conditions of low oxygen tension in CPVs; 3) vasorelaxation is attenuated by the NO-scavenging effect of oxyHb and abolished by sGC inhibition in chorionic plate arteries (CPAs) and 4) nitrite reduction to NO does not occur via any of the candidate nitrite reductase (NiR) enzymes investigated to date, including xanthine oxidoreductase, mitochondrial aldehyde dehydrogenase, mitochondrial bc1 complex or NO synthase (NOS) enzymes
We found that selective inhibitors of xanthine oxidoreductase, mitochondrial aldehyde dehydrogenase, mitochondrial bc1 complex and NOS enzymes did not block nitrite-induced vasorelaxation in CPAs or CPVs under conditions of hypoxia
Summary
Nitric oxide (NO) is a potent endogenous vasodilator important in the regulation of vasomotor tone, blood flow and systemic blood pressure [1]. Circulating nitrite is taken up by blood vessels and other tissues and subsequently converted to NO-related products, Nitric Oxide 80 (2018) 82–88 which can be bioactivated to generate NO [4] This is enhanced under conditions in which the physiological oxygen-dependent NOS enzyme activities are impaired [5], such as in hypoxia [6] or ischemia [7,8]. The importance of this ‘alternative’ pathway for NO production from nitrite has opened up a growing avenue for research where the use of nitrate/nitrite supplementation or nitrite delivery aims at improving NO bioavailability and bioactivity in diseases associated with local vasoconstriction and hypoxia
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