Vitamin B3 Nicotinamide: A Promising Candidate for Treating Preeclampsia and Improving Fetal Growth

Abstract

Up to 8% of pregnant women suffer from preeclampsia (PE), a deadly disease characterized by high blood pressure (BP), blood vessel damage, called endotheliosis (vascular endothelial swelling with narrowing of capillary lumen), and high levels of protein in the urine. PE is often associated with premature delivery, which is a risk factor of cardiovascular and metabolic diseases among the offspring. Accordingly, establishing drug treatments of PE is in immediate needs. Currently, many of anti-hypertensive drugs cause malformation of the fetuses and are contraindicated for pregnant women. Anti-hypertensive drugs that are allowed to be used for treating pregnant women could lower BP of the mothers and reduce the risk of maternal death due to cardiovascular diseases such as cerebral hemorrhage. However, these anti-hypertensives do not improve endotheliosis and proteinuria. In fact, they reduce blood supply to the placentae and fetuses, which could lead to fetal growth restriction (FGR) and fetal and neonatal death. Until now, the only treatment for preeclamptic women has been delivery of the baby and placenta. Using three mechanistically different mouse models of PE, we have found that vitamin B₃ nicotinamide (Nam) is the first safe drug that alleviates PE, and that Nam also alleviates or prevents miscarriage, prolongs pregnancy period, and improves the growth of the fetuses in mice with PE. Importantly, Nam has been used for pregnant and nursing women who have difficulty in taking sufficient meal. Nam could help treat or prevent PE and FGR associated with PE, if the treatment works in humans.

Keywords: endotheliosis; fetal growth restriction; nicotinamide; preeclampsia; premature delivery.

Fig. 1.. Endotheliosis of kidney glomerular capillary.

Glomerular capillary from a control mouse (A). Glomerular capillary from a preeclamptic mouse overexpressing the soluble form of VEGF receptor-1 (sVEGFR-1, commonly referred to as sFlt-1) sFlt-1 (B). Glomerular capillary in the kidney from preeclamptic mice has characteristic feature of endotheliosis: swelling of endothelial cells and narrowing of capillary lumen.

Fig. 2.. Pathogenesis of preeclampsia.

The pathogenesis of preeclampsia (PE) is not fully known, but when the invasion of trophoblast into spiral arteries is poor, flaccid low resistance arteries do not develop, and placenta and fetus become ischemic, which increases the expression of sFlt-1 in the placenta. sFlt-1 is the soluble VEGF (vascular endothelial growth factor) receptor 1, which lacks transmembrane and cytosolic domains, and is secreted into the circulation. Because sFlt-1 has ligand binding domain, VEGF binds to sFlt-1, and cannot bind to full length VEGF receptor 1 (VEGFR1) and VEGFR2. sFlt-1 works as an antagonist of VEGF. sFlt-1 overexpression model using adenovirus is a wildly used model of PE.

Fig. 3.. Nicotinamide (Nam) inhibits vasoconstriction by endothelin (ET-1).

Although inhibiting type 1 ET receptor (ETAR) is not suitable for pregnant women, inhibiting part of its signaling could help treating PE without adverse effects. Nam is known to inhibit vasoconstriction by ET-1 through inhibiting adenosine diphosphate (ADP) ribosyl cyclase, and reducing its product cyclic ADP ribose (cADPR) and Ca²⁺ mobilization. Because Nam is not teratogenic, it would be a promising drug to treat PE patients. Modified from Thai and Arendshorst (2008).

Fig. 4.. Nam is anti-oxidant and likely decreases BP.

Nicotinic acid increases heme oxygenase-1 (HO-1) expression, and decreases BP. The same could be true for Nam. HO degrades heme and produces carbon monoxide and biliverdin/bilirubin. These are antioxidants, and Nam likely ameliorates PE by reducing oxidative stress.

Fig. 5.. Nam ameliorates PE induced by sFlt-1 in mice.

sFlt-1 increases BP and urinary albumin excretion. Nam inhibited these changes, and corrected endotheliosis. Modified from Li et al. (2016).

Fig. 6.. Nam prolongs pregnancy duration and corrects fetal growth restriction (FGR).

Nam prolongs pregnancy period. Nam does not change body weight of fetuses in the absence of sFlt-1. But when sFlt-1 is overexpressed fetal body weight decreased and Nam corrected it to the control levels. Modified from Li et al. (2016).

Fig. 7.. Mouse reduced uterine perfusion pressure (RUPP) model of PE.

Uterine arteries and veins (U, U’) are constricted to reduce uterine blood flow. Modified from Fushima et al. (2016).