Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3+/Pod+/CD11b+ Cells) in Patient with Preeclampsia

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.

Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

“…One common tissue engineering-based approach involves 3D hydrogels that can support LEC spheroids (Figure 3B) to monitor lymphatic sprouting over time as an indicator of lymphangiogenic activity. [148][149][150] Alternatively, cells-LECs and stromal cells-can be encapsulated and distributed throughout 3D hydrogels, which may result in LECs forming tube-like or capillary-like structures. Encapsulated cells can also be evaluated on their migratory behavior through a 3D hydrogel that mimics an interstitial ECM or assessed for phenotypic changes in response to altered ECM properties.…”

The Impact of Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease

“…As an important source of LEPCs, the isolation of peripheral blood cells can successfully acquire two distinguishable circulating progenitors, including classical endothelial progenitors (high-level expression of VEGFR-1 but low-level VEGFR-3) and LEPCs (high-level expression of PROX-1, VEGFR-3, Podoplanin, and LYVE-1 but low-level VEGFR-1) [ 70 ]. In addition, the existence of an analogous group (VEGFR3 + /Podoplanin + /CD11b + LEPCs) has also been confirmed in human umbilical cord blood [ 71 ].…”

Decidual lymphatic endothelial cell‐derived granulocyte‐macrophage colony‐stimulating factor induces M1 macrophage polarization via the NF‐κB pathway in severe pre‐eclampsia

“…Lymphatics at the maternal‐fetal interface are key factors involved in the regulation of immune cell trafficking and antigen presentation, all of which may affect the acquisition of immune tolerance during pregnancy 15–18 . In previous studies, we demonstrated that the distribution of decidual lymphatics and that the lymphangiogenic function of lymphatic endothelial cells (LECs) are reduced in PE 19,20 . LECs, which comprise lymphatic vessels in the tissue and lymph node, interact with innate and adaptive immune cells, both in the tissue and in the lymph node 21,22 .…”

“…[15][16][17][18] In previous studies, we demonstrated that the distribution of decidual lymphatics and that the lymphangiogenic function of lymphatic endothelial cells (LECs) are reduced in PE. 19,20 LECs, which comprise lymphatic vessels in the tissue and lymph node, interact with innate and adaptive immune cells, both in the tissue and in the lymph node. 21,22 LECs may help modulate inflammation and adaptive immune responses through their interactions with macrophages.…”