期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 11, 页码 4912-4921出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI120446
关键词
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资金
- NIH [R01 HD060860, HD020676, HD079363, HL073402, HL120872, F31 HD095585]
- Kirschstein-NRSA training grant [T32 2T32HL069768-16]
- Lendulet program of the Hungarian Academy of Sciences [LP2014-4/2018]
- National Research, Development and Innovation Office [NVKP_16-2016-1-0039]
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 Flt4(chy/+) mice with kinase inactive VEGFR3 and Vegfc(fl/fl) Vav1-Cte 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.
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