Preeclampsia is a multi-organ complication of late pregnancy that is typically characterized by gestational hypertension and proteinuria. In severe cases, eclamptic seizure, liver and/or renal failure, and death can occur. This devastating disorder affects between 5 % and 7 % of all pregnancies and results in approximately 76,000 deaths of mothers and 500,000 deaths of babies each year, worldwide.[1] Even after recovering from preeclampsia, patients have an increased risk of cardiovascular and metabolic disease throughout their lifespan, as well as increased risk for peripartum anxiety and depression. In fact, depression and preeclampsia each portend upwards of a three-fold increased risk for the other.[2], [3], [4], [5], [6], [7] However, underlying mechanisms which link this bidirectional psycho-obstetric risk remain unclear.

One possible overlapping mechanism which may link risk for depression with that for preeclampsia is serotonin-immune dysfunction, as we have detailed previously.[8] Dysregulated serotonin signaling across organ systems and among immune cells may lead to vascular damage and dysfunction, both peripherally and in the brain, which is prolonged even years after the index preeclamptic pregnancy.[9], [10] Identifying antecedent mechanisms which might drive downstream hyperserotonemia, vascular dysfunction, and psycho-obstetric risk is critical to advancing treatment, prevention, and therapeutic options.

The serotonin-immune response to pregnancy, which is disrupted in depression [8], [11], and vascular endothelial damage seen in preeclampsia are linked via the hemeprotein idoleamine 2,3 dioxygenase (IDO). IDO is an enzyme which converts tryptophan to kynurenine; IDO acts as a catalyst at the rate limiting step of tryptophan breakdown, which is dysregulated in preeclampsia and depression.[8], [12] Tryptophan, a necessary amino acid for T-cell function, is depleted when sufficient IDO is present, therefore suppressing the proliferation of T-cells.[13] IDO inhibition thereby leads to increased tryptophan availibility for serotonin synthesis.

IDO is secreted by placental trophoblasts, decidua, and immune cells, and plays a major role in the suppression of T-cell mediated responses to pregnancy. IDO expression at the maternal-fetal interface is detectable as early as the 14th week of gestation and continues throughout pregnancy [14], with increased levels detected in term relative to preterm chorionic tissues.[15] In normal pregnancy, IDO-mediated suppression of cytotoxic T-cells increases the tolerance of the host to foreign antigens, and in the case of pregnancy, it decreases maternal host rejection of the allogenic feto-placental unit.[16] When IDO is blocked, complete fetal rejection occurs.[16] Inflammatory dysregulation is a key endopathologic feature of both depression and preeclampsia, interacts with IDO activation, and is a promising therapeutic target for both conditions.[17], [18], [19].

IDO is also involved in the vascular oxidative damage that occurs in preeclampsia and depression.[20], [21], [22], [23] IDO may prevent damage by utilizing superoxide anion (O2●-) radicals as it catabolizes L-tryptophan.[24] It therefore follows that decreased IDO leads to increased O2●-, which can contribute to oxidative endothelial damage and persistent endothelial dysfunction.[25], [26], [27] Relative to healthy pregnancies, preeclamptic pregnancies result in abnormal flow mediated vasodilation, an index of endothelial function, for up to one year postpartum.[28].

IDO dysfunction may be a viable clinical target for the prevention, treatment, and management of psycho-obstetric risk. Santoso and colleages[29] found that women with preeclampsia have decreased placental IDO activity, and Santillan and colleagues[30] demonstrated that mice lacking IDO exhibit clinically-relevant preeclampsia phenotypes. A similar body of literature suggests that IDO activity in the hippocampus is related to depressive-like behaviors in animal models, and that IDO activity is modulated by antidepressant drugs in humans.[31], [32].

This evidence led us to hypothesize that IDO plays a key role in the pathogenesis of poor vascular function in preeclampsia and depression. Given the central and convergent mechanistic role of IDO in oxidative and inflammatory processes implicated in psycho-obstetric disease pathogenesis, IDO manipulation may be a promising target in treatment and prevention. Therefore, the objective of the present study was to determine if women with low circulating plasma IDO activity in pregnancy would also exhibit vascular stiffness. Increased vascular stiffiness has been reported both during and following a preeclamptic pregnancy in cohorts across the world, and is a robust disease endophenotype. [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44] Vascular stiffness is one measure of endothelial function, which we measure here via carotid-femoral pulse wave velocity.[40].

Preeclampsia is linked to a three-fold increased risk for maternal depression, possibly via serotonergic-vascular mechanisms.[8], [11] Vascular changes similar to those reported in preeclampsia have also been reported in major depressive disorder.[45] Given these interactions between IDO activity, serotonin systems, and psychiatric health, we further sought to determine whether depression symptoms in pregnancy were associated with IDO activity. We predicted that women who exhibit low circulating IDO activity early in pregnancy would have decreased late-pregnancy vascular function (i.e., higher arterial stiffness), and that low IDO would be associated with increased depression symptoms.