Abstract
The abnormal development or disruption of the lymphatic vasculature has been implicated in metabolic and hypertensive diseases. Recent evidence suggests that the offspring exposed to preeclampsia (PE) in utero are at higher risk of long-term health problems, such as cardiovascular and metabolic diseases in adulthood, owing to in utero fetal programming. We aimed to investigate lymphangiogenic activities in the lymphatic endothelial progenitor cells (LEPCs) of the offspring of PE. Human umbilical cord blood LEPCs from pregnant women with severe PE (n = 10) and gestationally matched normal pregnancies (n = 10) were purified with anti-vascular endothelial growth factor receptor 3 (VEGFR3)/podoplanin/CD11b microbeads using a magnetic cell sorter device. LEPCs from PE displayed significantly delayed differentiation and reduced formation of lymphatic endothelial cell (LEC) colonies compared with the LEPCs from normal pregnancies. LECs differentiated from PE-derived LEPCs exhibited decreased tube formation, migration, proliferation, adhesion, wound healing, and 3D-sprouting activities as well as increased lymphatic permeability through the disorganization of VE-cadherin junctions, compared with the normal pregnancy-derived LECs. In vivo, LEPCs from PE showed significantly reduced lymphatic vessel formation compared to the LEPCs of the normal pregnancy. Gene expression analysis revealed that compared to the normal pregnancy-derived LECs, the PE-derived LECs showed a significant decrease in the expression of pro-lymphangiogenic genes (GREM1, EPHB3, VEGFA, AMOT, THSD7A, ANGPTL4, SEMA5A, FGF2, and GBX2). Collectively, our findings demonstrate, for the first time, that LEPCs from PE have reduced lymphangiogenic activities in vitro and in vivo and show the decreased expression of pro-lymphangiogenic genes. This study opens a new avenue for investigation of the molecular mechanism of LEPC differentiation and lymphangiogenesis in the offspring of PE and subsequently may impact the treatment of long-term health problems such as cardiovascular and metabolic disorders of offspring with abnormal development of lymphatic vasculature.
Highlights
These results demonstrate that vascular endothelial growth factor receptor 3 (VEGFR3)+ /Pod+ /CD11b+ cells from cord blood can serve as lymphatic endothelial progenitor cells (LEPCs) that can differentiate into lymphatic endothelial cell (LEC)
Found to be significantly down-regulated in the LECs derived from preeclamptic pregnancies (Figure 8B,C). These results suggest that the down-regulated expression of various lymphangiogenesis-related genes may be related to the decreased lymphangiogenic function of LECs from preeclamptic pregnancy
In relation to neurodevelopmental diseases, malfunction of the lymphatic vessel has been associated with autism spectrum disorder, which is more common in offspring exposed to PE [50,51]. In light of these previous reports, the present study provides important evidence that PE is a critical factor related to dysfunctional lymphangiogenesis in offspring, mediated via a reduction in the lymphangiogenic capacity and function of LEPCs and LECs, which may substantially affect the long-term health of offspring
Summary
Several studies have suggested that in utero fetal programming that compromises the intrauterine environment may permanently alter the structure and function of the biological system of the fetus, increasing the individual’s susceptibility to disease later in life. Previous studies have reported epigenetic modifications and/or altered gene expression in the fetal endothelial progenitor cells (EPCs) exposed to PE in utero. These changes were associated with diminished proliferation, increased senescence, or abnormal endothelial cell function [17,18,19,20,21]. Changes in cellular behavior that culminate in dysfunctional angiogenesis may serve as one of the possible mechanisms underlying compromised in utero programming in the case of severe PE [22,23,24,25]
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