TSP-1 Endothelial Signaling Impairs Brain Angiogenesis in Preeclampsia.

Abstract

Background: Preeclampsia adversely affects fetal brain angiogenesis, with potential acute and long-term consequences. However, the mechanisms underlying these cerebrovascular alterations remain unclear. We investigated whether TSP-1 (thrombospondin-1), an antiangiogenic glycoprotein, mediates communication between fetoplacental and fetal brain endothelium in preeclampsia.

Methods: Conditioned media from human umbilical vein endothelial cells derived from normal and preeclamptic pregnancies were used to treat human (human cerebral microvascular endothelial cell line) and murine brain endothelial cells. Proteomic analysis of umbilical cord serum identified differentially expressed proteins, and TSP-1 was validated by Western blot. TSP-1 expression was investigated in umbilical endothelial cells (EA.hy926) exposed to umbilical cord serum TSP-1 depletion and antibody-mediated blockade were used to evaluate its role in angiogenesis and downstream signaling pathways.

Results: Conditioned media from fetal endothelial cells of preeclamptic pregnancies reduced angiogenesis (P<0.05), migration, and invasion of brain endothelial cells and disrupted cytoskeletal organization. These effects were associated with decreased signaling via vascular endothelial growth factor receptor 2 (P<0.05). TSP-1 was elevated in serum and conditioned medium from preeclampsia (P<0.05). Exposure of EA.hy926 to serum from preeclamptic pregnancies significantly increased TSP-1 protein levels compared with normal pregnancy serum. Antibody-mediated blockade of TSP-1 restored angiogenesis (P<0.001) and rescued vascular endothelial growth factor receptor 2 signaling in brain endothelial cells exposed to conditioned media from preeclampsia.

Conclusions: Our findings support TSP-1 as a key contributor to placenta-brain vascular communication in preeclampsia, in which it impairs angiogenic signaling and reduces fetal brain angiogenesis. This mechanism may contribute to acute and long-term cerebrovascular dysfunction in offspring of preeclampsia.