Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

Abstract

Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α–induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved.

The prediction of fetal death with a simple maternal blood test at 24-28 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio)

“…Other interventions that could be effective include metformin 181 and proton pump inhibitors. 182, 183 …”

Neurodevelopment at Age 10 Years of Children Born <28 Weeks With Fetal Growth Restriction

“…Low-dose aspirin administered in early gestation has therapeutic benefits for some women who are at increased risk of preeclampsia (and its correlates [ie, FGR] 135 ), and trials are underway to test additional strategies. 135 -140 Placental and other stem cells, 141 -148 proton-pump inhibitors, 149 low-molecular-weight heparin 150 and other molecules 151 -153 might also have therapeutic benefits. Indeed, compelling studies of rodents 154 -157 and nonhuman primates 158 support the possibility of a therapeutic benefit from exogenous angiotrophins during gestation.…”

Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With Impaired PP13 Molecule or Function

“…This includes a number of compounds unrelated to treating CVDs. Among them is Sofalcone, a drug currently tested only in tissue culture that potently activates the antioxidant nuclear factor (erythroid-derived 2)-like 2/HO-1 pathway, decreases sFlt-1 production, and ameliorates endothelial dysfunction [62].…”