Samantha Pozo Navarro

Background: Preeclampsia is a complex, new-onset hypertensive disorder that affects 3-8% of all pregnancies worldwide.¹ In this case, hypertension is defined when the mother’s systolic blood pressure is greater than or equal to 140 mmHg and/or her diastolic blood pressure is greater than or equal to 90 mmHg after approximately 20 weeks of gestation.² This disorder causes 20-30% of all preterm births.² Preeclampsia does not have a single specific cause but rather is the result of multiple pathologic processes that cause a pro-inflammatory environment at the maternal-fetal interface.³ The in-utero environment can have long term consequences for the offspring. For example, fetuses exposed to preeclampsia have an 8% increased risk of mortality from ischemic heart disease and a 12% increased risk of strokes in their adult life.”² Currently, the only definitive treatment is delivery of the baby.

Objective: In this narrative review, we aimed to investigate lymphangiogenic activities in lymphatic endothelial progenitor cells (LEPCs) of offspring who have been exposed to preeclampsia in an effort to provide insight into a potential mechanism by which the in-utero fetal exposure results in reprogramming of fetal physiology and contributes to cardiovascular disease susceptibility in adulthood.

Search Methods: An online search in the PubMed database was conducted for articles from 2018 to 2022 using the following keywords “lymphatic endothelial cells in preeclampsia,” “cardiovascular disease in preeclampsia,” and “lymphangiogenesis in cardiovascular disease”.

Results: Studies indicate that during embryo implantation, various alterations of the decidua occur to create a proinflammatory environment. One such alteration was reported in a study where tubular lymphatic vessel density was significantly reduced in the decidua of women with preeclampsia.⁴ A correlation was made between lymphatic vessel density and the level of Tregs whereby a decrease in lymphatic vessel density correlated with a decrease in FOXP3+ expressing Tregs.⁴ Additionally, it has also been reported that type 1 macrophage markers predominate in the decidua of women with preeclampsia which further contributes to the inflammatory processes in this disorder.⁵ The fetal physiologic response to such conditions was analyzed by studying a lymphatic endothelial progenitor cell (LEPC) line taken from human cord blood cells identified as VEGFR3+ /Pod+ /CD11b+ Cells.⁶ The LEPCs from normal pregnancies differentiated into lymphatic endothelial cells (LECs) after 9 days in culture; however, those cells taken from preeclamptic pregnancies differentiated after 14 days in culture.⁶ The LEPCs from preeclamptic pregnancies also showed a significantly reduced density of lymphatic vessel specific markers.⁶ Another independent study highlighted the contributions of abnormal lymphangiogenesis to the pathogenesis of cardiovascular disease in zebrafish.⁷ VEGFC and VEGFD contribute to the development of lymphatic vessels in the heart; therefore, VEGFC and VEGFD mutants that lacked functional lymphatic vessels showed cardiac hypertrophy without previous injury and a significantly reduced ability of the heart to resolve inflammation.⁷ These findings may point to a similar mechanism in humans.

Conclusions: The reprogramming of the fetal lymphatic framework due to in-utero exposure to preeclampsia sets the stage for future investigations of molecular mechanisms of LEPC differentiation and lymphangiogenesis. Future treatments of cardiovascular diseases in adults who were exposed to preeclampsia in-utero can potentially include lymphatic interventions even before patients present with cardiac complications.

Works Cited:

1. Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia-Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;76(14):1690-1702. doi:10.1016/j.jacc.2020.08.014
2. Fox R, Kitt J, Leeson P, Aye CYL, Lewandowski AJ. Preeclampsia: Risk Factors, Diagnosis, Management, and the Cardiovascular Impact on the Offspring. J Clin Med. 2019;8(10):1625. Published 2019 Oct 4. doi:10.3390/jcm8101625
3. Jung E, Romero R, Yeo L, et al. The etiology of preeclampsia. Am J Obstet Gynecol. 2022;226(2S):S844-S866. doi:10.1016/j.ajog.2021.11.1356
4. Jung YJ, Park Y, Kim HS, et al. Abnormal lymphatic vessel development is associated with decreased decidual regulatory T cells in severe preeclampsia. Am J Reprod Immunol. 2018;80(1):e12970. doi:10.1111/aji.12970
5. Wheeler KC, Jena MK, Pradhan BS, et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One. 2018;13(1):e0191040. Published 2018 Jan 11. doi:10.1371/journal.pone.0191040
6. Kwon H, Kwon JY, Song J, Maeng YS. Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3⁺/Pod⁺/CD11b⁺Cells) in Patient with Preeclampsia. Int J Mol Sci. 2021;22(8):4237. Published 2021 Apr 19. doi:10.3390/ijms22084237
7. Vivien CJ, Pichol-Thievend C, Sim CB, et al. Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context. NPJ Regen Med. 2019;4:18. Published 2019 Aug 22. doi:10.1038/s41536-019-0079-2