Role of ADAMTS13 and von Willebrand factor in pathogenesis of experimental preeclampsia in rats Free

Introduction: Preeclampsia, a serious complication of pregnancy that occurs at ≥20 weeks of gestation, is characterized primarily by hypertension and proteinuria with increased rates of perinatal morbidity and mortality. While preeclampsia is recognized as a multisystem disorder, likely associated with insufficient extravillous trophoblast (EVT) cell invasion into spiral arteries and placental thrombosis, the molecular mechanisms underlying its pathogenesis remain poorly understood.

ADAMTS13 plays a critical role in hemostasis by cleaving von Willebrand factor (VWF), thereby regulating platelet adhesion and preventing excessive microvascular thrombosis. Deficiency of plasma ADAMTS13 activity, whether due to genetic mutations or acquired autoantibodies, leads to uncontrolled platelet adhesion and aggregation, a key driver in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). Previous studies have demonstrated both ADAMTS13 and VWF are expressed in trophoblast and vascular endothelial cells, with the levels varying across different stages of gestation, suggesting that the ADAMTS13 and VWF balance may play an important role in the pathogenesis of preeclampsia. However, the experimental proof is still lacking.

Objectives: The present study aims to test ahypothesis that imbalance in ADAMTS13 and VWF may be involved in the pathogenesis of preeclampsia by affecting trophoblast cell development that results in compromised placental blood perfusion.

Methods: To test this hypothesis, we developed a rat model of preeclampsia by daily subcutaneous injection of N-nitro-L-arginine methyl ester (L-NAME) during the second half of gestation. Systolic blood pressure was measured following arterial catheterization. Placentas, kidneys, and urine samples were collected at the designated gestation time point for hematoxylin–eosin (H&E) staining and immunohistochemistry (IHC) to evaluate the location and extent of placental thrombosis, as well as the expression and distribution of VWF within placental tissues. Western blot analysis was conducted on placental protein extracts to determine changes in ADAMTS13 expression.

Results: Compared with the buffer control group, L-NAME–treated rats exhibited significantly elevated systolic and diastolic blood pressure and increased urinary protein concentration. Both placental and fetal weights were markedly reduced in the L-NAME group. Histologic analysis revealed renal glomerular structural collapse with irregular morphology. Immunohistochemistry demonstrated a dramatic increase in the number of fibrin- and platelet-rich thrombi in placental tissue, particularly within spiral arteries of the uterine-placental interface region. Moreover, immunohistochemistry revealed significantly increased VWF expression and deposition along the vessel walls of spiral arteries in L-NAME–treated rats compared with the buffer controls. Western blotting showed a marked reduction of placental ADAMTS13 expression in L-NAME-treated placentas compared with buffer controls.

Conclusions: We demonstrate the success in establishment of a rat preeclampsia model by a subcutaneous administration of L-NAME. These rats present with hypertension, proteinuria, and placental and fetal growth restriction resulting from extensive thrombosis within placentas, especially in spiral arteries. The marked reduction in placental ADAMTS13 expression, together with excessive VWF expression and deposition supports the hypothesis that a dysregulation of the ADAMTS13–VWF axis may play a role in the pathogenesis and progression of preeclampsia.