Hypoxic Stress Causes an Increase in Microvesicles Leading to Placental Endothelial Dysfunction in Preeclampsia
Introduction: Preeclampsia is a pregnancy-induced disorder defined as new-onset hypertension (>140/90 mmHg) and one of the following after 20 weeks of gestation: proteinuria, most commonly; thrombocytopenia; renal insufficiency; impaired liver function; persistent abdominal pain; or pulmonary edema.1 Preeclampsia affects 5-8% of pregnancies and is a leading cause of maternal morbidity and mortality in the U.S.1 Severe, untreated cases may progress into eclampsia causing seizures and potential neurological damage to the mother and fetus.1 Currently, the only definitive treatment is delivery of the fetus and placenta.2 Symptom management using antihypertensive medications is moderately effective at controlling the disorder, but conclusive diagnostic and therapeutic methods are needed.2 Hypoxic stress increasing placental microvesicle release and creating an imbalance of factors promoting and inhibiting angiogenesis, such as VEGF and vesicle-bound Flt-1, respectively, is central to the pathogenesis of preeclampsia and thus is a promising treatment target.3 Methods: Placental extracellular vesicles (EVs) were collected from normotensive and preeclamptic human placentae.4 The placental tissue was cultured, then EVs were separated by size as either nano-, micro-, or macrovesicles using centrifugation.4 Total proteins were extracted and probed with anti-human Flt-1 and antibodies for protein visualization.4 ELISA assays were used to quantify levels of VEGF and Flt-1 present in the placental culture.4 ELISA assays for ICAM-1 and monocyte adhesion were also performed to investigate if the target of EVs was endothelial cells.4 Results: Compared to normotensive samples, preeclamptic placentae released a greater number of micro- and nanovesicles, and the size of the microvesicles was increased.4 Flt-1 is known to be one of the proteins carried by EVs, and its levels were found to be elevated in each trimester of gestation in both micro- and nanovesicles as compared to healthy placentae.1,4 Flt-1 levels were determined to be correlated positively with severity of preeclampsia, determined by the degree of maternal hypertension and proteinuria, as well.4 This can be explained by the fact that vesicle-bound Flt-1 sequesters VEGF and prevents it from promoting placental angiogenesis.4 Additionally, all three sizes of EVs increased endothelial surface expression of ICAM-1 and monocyte adhesion, indicating that the EVs activate endothelial cells.4 Conclusion: The over-release of placental microvesicles creating an imbalance between pro- and anti-angiogenic factors VEGF and vesicle-bound Flt-1, respectively, contribute to the endothelial dysfunction observed in preeclampsia. This widespread endothelial damage is part of the mechanism leading to hypertension and proteinuria, which suggests that both VEGF and Flt-1 may be diagnostic markers that allow for early intervention and serve as novel therapeutic targets.
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- Gupta M, Feinberg BB, Burwick RM. Thrombotic microangiopathies of pregnancy: Differential diagnosis. Pregnancy Hypertens. 2018;12:29-34. doi:10.1016/j.preghy.2018.02.007
- Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol. 2019;15(5):275-289. doi:10.1038/s41581-019-0119-6
- Tong M, Chen Q, James JL, Stone PR, Chamley LW. Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia. Front Endocrinol (Lausanne). 2017;8:174. Published 2017 Jul 24. doi:10.3389/fendo.2017.00174