A new Japanese study's findings cast light on the role of intracellular signaling mediated by reactive oxygen species (ROS) in maintaining placental angiogenesis, which may explain the failure of clinical trials of antioxidants in preeclampsia and supports their use for the currently untreatable condition.

Characterized by acute hypertension with damage to major organs, preeclampsia affects 3 percent to 8 percent of pregnancies with varying severity, causes 10 to 15 percent of all perinatal mortality, is a major cause of fetal intrauterine growth retardation, and can even persist in women after delivery.

However, despite that marked impact on both maternal and infant health, there remain no effective treatments for preeclampsia that can prolong pregnancy, without adversely affecting fetal health and development.

However, despite that marked impact on both maternal and infant health, there remain no effective treatments for preeclampsia that can prolong pregnancy, without adversely affecting fetal health and development.

"While antihypertensives can be used in some cases of preeclampsia, they are not so effective," lead researcher Norio Suzuki told BioWorld Today.

"It is thought that defects in placental angiogenesis may cause hypertension, in order to deliver enough amounts of oxygen and nutrients into the fetus through the poor vascular network in preeclamptic placentas," explained Suzuki, who is an associate professor in the Division of Oxygen Biology at Tohoku University Graduate School of Medicine in Sendai, Japan. "Therefore, antihypertensives are unsuitable for preeclampsia treatment."

Placental activation of the renin-angiotensin system (RAS) is known to play a key role in the pathogenesis of preeclampsia, while ROS are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology.

Excess ROS accumulation also induces oxidative stress, resulting in excessive inflammation, which is considered a major causative factor in preeclampsia pathophysiology through induction of poor placental perfusion and maternal endothelial dysfunction.

Nevertheless, large clinical trials of strategies aimed at reducing oxidative stress with antioxidants have been repeatedly negative or even had adverse fetal outcomes. That brings into the question the role of oxidative stress and ROS in preeclampsia, with one possibility being that ROS acts as a secondary messenger to some other signaling mechanism.

In their new study, Suzuki and his research team investigated the role played by the Kelch-like erythroid-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) pathway in preeclampsia.

"The Keap1-Nrf2 pathway has been known to be the major pathway for cellular adaptation to oxidative stress for the past 20 years," said Suzuki. "Our recent studies in genetically modified mice have demonstrated that the system is essential for organ protection from damage in many types of diseases.

"Preeclampsia is a relatively frequent and intractable disorder, with hypertension being considered closely related to oxidative stress and accumulation of ROS. Therefore, we thought the cellular antioxidant system might be involved in the pathogenesis and progression of preeclampsia and its complications, hence the rationale for this study."

The research team genetically modified the Keap1-Nrf2 pathway in a mouse model of RAS-induced preeclampsia, they reported in the May 16, 2017, online edition of Science Signaling.

Because the Keap1-Nrf2 pathway is important in ameliorating oxidative stress and regulating the antioxidant defense system, Nrf2 deficiency should impair the cellular antioxidant response. However, in preeclamptic mice, Nrf2 deficiency improved maternal and fetal survival, and ameliorated intrauterine growth retardation

"Maternal death due to preeclampsia was reduced from 30 percent to less than 5 percent by Nrf2 knockout, while neonatal death was halved," said Suzuki. Furthermore, "fetal body weight was reduced by approximately 10 percent by preeclampsia in mice, which Nrf2 knockout restored to normal levels."

Nrf2 deficiency was also found to augment oxidative DNA damage in the preeclamptic placentas, confirming their high level of oxidative stress. "Surprisingly, Nrf2 knockout ameliorated preeclampsia, even though oxidative DNA damage was highly accumulated in the placenta of preeclampsia mice lacking Nrf2," noted Suzuki.

In addition, the placentas of Nrf2-deficient mice were shown histologically to have increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines.

"We conducted a genome-wide microarray analysis of the mouse placentas, and discovered that expression levels of a set of genes encoding for angiogenic chemokines were commonly increased by Nrf2 knockout," said Suzuki.

"Since loss of placental vascularity is considered to be a major cause of preeclampsia, this suggests that oxidative stress-related induction of angiogenic factor expression is likely associated with improvement of preeclampsia by Nrf2 knockout."

Taken together, those findings support the concept that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may help to explain the negative results observed in clinical trials of antioxidants in preeclampsia.

In the future, further studies and the use of additional models of preeclampsia may lead to a better understanding of the role of ROS signaling in humans with preeclampsia and its management, said Suzuki.

"The molecular mechanisms of placental angiogenesis regulated by oxidative stress remain unclear. By studying the molecular mechanisms of preeclampsia, we will better understand its pathology. Drugs inhibiting the cellular antioxidant system are therefore plausible candidates for preeclampsia treatment in future," he added.

"We have already screened and identified chemical compounds that inhibit Nrf2 activity in rodents and we are now planning to investigate whether these Nrf2 activators improve preeclampsia in the mouse model."