Lymphatic mimicry in maternal endothelial cells promotes placental spiral artery remodeling

• Published in: The Journal of clinical investigation Vol. 129; no. 11; pp. 4912 - 4921
• Main Authors: Pawlak, John B, Bálint, László, Lim, Lillian, Ma, Wanshu, Davis, Reema B, Benyó, Zoltán, Soares, Michael J, Oliver, Guillermo, Kahn, Mark L, Jakus, Zoltán, Caron, Kathleen M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.11.2019
• Subjects: Animals; Antigens, Differentiation; Arteries; Arteries - immunology; Arteries - pathology; Biomedical research; Cancer; Cell adhesion & migration; Endothelial cells; Endothelium; Endothelium, Lymphatic - immunology; Endothelium, Lymphatic - pathology; Extracellular matrix; Female; Fetal development; Fetal Growth Retardation - immunology; Fetal Growth Retardation - pathology; Fetuses; Gestation; Hormones; Humans; Kinases; Mice; Mimicry; Molecular Mimicry; Natural killer cells; Novels; Phosphorylation; Physiological aspects; Physiology; Placenta; Placenta - blood supply; Placenta - immunology; Placenta - pathology; Pre-eclampsia; Pre-Eclampsia - immunology; Pre-Eclampsia - pathology; Preeclampsia; Pregnancy; Pregnancy complications; Smooth muscle; Sunitinib; Uterus; Uterus - blood supply; Uterus - immunology; Uterus - pathology; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Vascular Remodeling - immunology; Veins & arteries; Mouse models; Reproductive biochemistry; Vascular Biology; Reproductive Biology; Lymph
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci120446

Molecular heterogeneity of endothelial cells underlies their highly specialized functions during changing physiological conditions within diverse vascular beds. For example, placental spiral arteries (SAs) undergo remarkable remodeling to meet the ever-growing demands of the fetus - a process which is deficient in preeclampsia. The extent to which maternal endothelial cells coordinate with immune cells and pregnancy hormones to promote SA remodeling remains largely unknown. Here we found that remodeled SAs expressed the lymphatic markers PROX1, LYVE1, and VEGFR3, mimicking lymphatic identity. Uterine natural killer (uNK) cells, which are required for SA remodeling and secrete VEGFC, were both sufficient and necessary for VEGFR3 activation in vitro and in mice lacking uNK cells, respectively. Using Flt4Chy/+ mice with kinase inactive VEGFR3 and Vegfcfl/fl Vav1-Cre mice, we demonstrated that SA remodeling required VEGFR3 signaling, and that disrupted maternal VEGFR3 signaling contributed to late-gestation fetal growth restriction. Collectively, we identified a novel instance of lymphatic mimicry by which maternal endothelial cells promote SA remodeling, furthering our understanding of the vascular heterogeneity employed for the mitigation of pregnancy complications such as fetal growth restriction and preeclampsia.