Abstract
Several recently published studies have suggested that decreasing VEGF levels result in placental oxidative stress in preeclampsia, although the question as to how decreased VEGF concentrations increase oxidative stress still remains unanswered. Here, we show that VEGF activated Nrf2, the main regulating factor of the intracellular redox balance, in the cytotrophic cell line BeWo. In turn, this activated the production of antioxidative enzymes thioredoxin, thioredoxin reductase, and heme oxygenase-1, which showed a decrease in their expression in the placentas of preeclamptic women. Nevertheless, this activation occurred without oxidative stress stimulus. As a consequence, the activation of Nrf2 protected BeWo cells against H(2)O(2)/Fe(2+)-induced oxidative damage. We further show that VEGF up-regulated the expression of itself. A positive feedback loop was described in which VEGF activated Nrf2 in an ERK1/2-dependent manner; the up-regulation of HO-1 expression by Nrf2 augmented the production of carbon monoxide, which in turn up-regulated VEGF expression. In conclusion, VEGF induces the Nrf2 pathway to protect against oxidative stress and, via a positive feedback loop, to elevate VEGF expression. Therefore, decreased VEGF bioavailability during preeclampsia may result in higher vulnerability to placental oxidative cell damage and a further reduction of VEGF bioavailability, a vicious circle that may end up in preeclampsia.