Preeclampsia is a serious complication of pregnancy. It is caused by placental inflammation and oxidative stress leading to sFlt-1 and soluble endoglin (sENG) secretion, inflicting widespread endothelial dysfunction and multisystem organ injury. The current treatment is delivery, which leads to morbidity and mortality associated with prematurity. A therapeutic that can stabilise preeclampsia would be a major advance. Sulfasalazine is a anti-inflammatory and antioxidant medication used to treat autoimmune disease. Importantly, it is safe in pregnancy. We examined whether sulfasalazine may be a therapeutic for preeclampsia. In particular, we examined its ability to reduce 1) sFlt-1 and soluble endoglin secretion and 2) endothelial dysfunction in vitro.
We administered increasing doses of sulfasalazine to primary trophoblasts and placental explants obtained from patients with preterm preeclampsia. Sulfasalazine significantly reduced sFlt-1 and sENG secretion in a dose dependent manner. This was accompanied by a reduction in mRNA expression of the placental specific variant sFlt1-e15a, and a reduction in mRNA expression of MMP14 (cleavage protease of endoglin). Sulfasalazine is known to inhibit inflammatory transcription factor NFkB and upregulate antioxidant enzyme heme oxygenase-1, and despite their overexpression or silencing respectively in primary trophoblasts, there was no change in sFlt-1 or sENG secretion.
We induced endothelial dysfunction by adding TNFα or preterm preeclamptic serum to primary HUVECs, and demonstrated a reduction in mRNA expression of vascular cell adhesion molecule 1 with sulfasalazine administration. Using the xCELLigence system (measures experiments in real time), we found sulfasalazine increased endothelial cell migration and improved proliferation. Sulfasalazine increased vasodilation of whole human omental vessels in the presence of a vasoconstrictor and improved angiogenesis from mouse aortic rings in the presence of sFlt-1.
In conclusion, sulfasalazine reduces placental sFlt-1 and sENG secretion. It rescues endothelial dysfunction, promotes human blood vessel dilation and rescues angiogenesis. Sulfasalazine may be a promising preeclampsia treatment.