Beyond the threshold: an etiological bridge between hypoxia and immunity in preeclampsia

Taking a cue from the recent workshop 'Preeclampsia--a Pressing Problem' sponsored by the National Institutes of Child Health and Human Development, this review article takes a fresh look at hypoxia and a dysfunctional immune system as the key contributors to the etiology of preeclampsia and the mechanisms involved therein. In the context of epidemiological research on the intricate and multifactorial nature of preeclampsia, we focus on hypoxia as an upstream regulator of preeclampsia and its consequences in a model compromised by a deficiency in key pregnancy compatible immune modulators. It has been proposed that placental hypoxia releases cytotoxic factors produced at the maternal-fetal interface into the circulation to manifest the maternal symptoms associated with preeclampsia. However, it is not clear how this mechanism is empowered in pregnant women. Does systemic hypoxia exert preeclampsia-like effects on pregnancy? Are these effects further manifested by intrinsic inflammation in the absence of key immune modulators such as IL-10? Thus, it is of paramount importance that in vivo models be developed wherein the role of systemic hypoxia can be evaluated for preeclampsia-causing events. We present a discussion on whether prolonged exposure to hypoxia can lead to a perpetual cycle of compartmentalized uteroplacental tissue damage, release of anti-angiogenic and vasoconstrictive factors that impair trophoblast invasion and promote systemic vascular resistance resulting in the maternal syndrome.