Lymphatic mimicry of spiral arteries is impaired by human sFLT1 overexpression in a preeclampsia mouse model.

Abstract

INTRODUCTION: The pregnancy disorder preeclampsia (PE) is characterized by maternal hypertension and reduced spiral artery (SpA) remodeling which is aggravated by increased levels of anti-angiogenic soluble fms-related tyrosine kinase 1 (sFLT1). One process contributing to physiological SpA remodeling in early pregnancy is the expression of lymphatic receptors on endothelial cells of SpAs, which is called lymphatic mimicry. Adverse lymphatic mimicry of SpAs is theorized to play a role in the pathophysiology of PE, but was not analyzed under preeclamptic conditions. METHODS: Using the transgenic PE/FGR mouse model with ubiquitous overexpression of human sFLT1 (hsFLT1), we focused on lymphatic marker expression in early pregnancy at 12.5 dpc and 14.5 dpc and evaluated the reduction of SpA remodeling as well as mRNA expression of lymphatic markers like Lyve1, Pdpn, or Prox1 in the mesometrial triangle (MT) of murine placentas. Additionally, uterine NK cell distribution was analyzed via electron microscopy and immunohistochemistry in placentas of PE animals. RESULTS: We could prove significantly reduced levels of Pdpn and Nrp1 mRNA in MT of PE placentas. Additionally, the mRNA expression of chemokines like Ccl21 were reduced at from 12.5 dpc until 14.5 dpc which could inhibit infiltration of uterine NK cell populations in these compartments in later pregnancy. DISCUSSION: With this study we could show that increased levels of human sFLT1 interfere with early spiral artery (SpA) remodeling processes and could inhibit lymphatic mimicry of SpA. Immune cell infiltration until 14.5 dpc could be decreased by downregulation of the chemotactic chemokine Ccl21.