Extrahepatic Synthesis of Factor VII in Human Atherosclerotic Vessels

Abstract

Objective— Coagulation is initiated by the interaction of tissue factor (TF) with plasma coagulation factors VII (FVII) and X (FX). TF is highly expressed in atherosclerotic lesions, but little is known about the synthesis of FX or FVII outside of the liver. Previous studies suggested that macrophages synthesize FVII. We therefore hypothesized that macrophages within atherosclerotic lesions may produce FVII, leading to partial activation of the coagulation cascade. Methods and Results— Immunohistochemistry was performed using antibodies against FVII, FX, and TF on normal and atherosclerotic vessels. In atherosclerotic lesions, FVII immunostaining was colocalized with TF in macrophages and spindle-shaped smooth muscle cells. FVII mRNA was also detected in these cells using in situ hybridization, suggesting the local synthesis of FVII in atherosclerosis. Reverse transcriptase–polymerase chain reaction confirmed the presence of FVII mRNA in normal and atherosclerotic vessels as well as smooth muscle cells, fibroblasts, and keratinocytes in vitro. Conclusions— The localization of FVII synthesis outside the liver may be indicative of other cellular functions for this coagulation protein. The observed coexpression of TF and FVII may contribute to autocrine signaling via thrombin-independent mechanisms and may represent a novel mechanism contributing to growth in the setting of vascular disease.