Kelbi Padilla

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.

1. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res. 2019;124(7):1094-1112. doi:10.1161/CIRCRESAHA.118.313276
2. 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
3. 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
4. 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