**1. Introduction**

Stabilin-1 (Stab1), belongs to a family of scavenger receptors, is a type 2 macrophage marker and is expressed in tissue macrophages and different endothelial cell subtypes [1–3]. Stabilin-2 (Stab2) belongs to the same family of scavenger receptors and shares 55% identity with Stab1 at the protein level [1,2,4,5]. Both Stab1 and Stab2 are expressed in macrophages and endothelial cells of various organs, including the liver and spleen [6,7]. Stab1 acts as a scavenger receptor for clearing debris and apoptotic cells through macrophage phagocytosis and is involved in the transcytosis of several components, including placental lactogen (PL) [1,3,8,9]. Stab1 modulates angiogenesis, supports leukocyte adhesion and transmigration, and regulates immune responses [1,3,9]. Stab2 is involved in clearing noxious blood factors and degrading apoptotic cells [10]. Stab2 also regulates extracellular matrix turnover and hyaluronan resorption to maintain body fluids, and participates in the defense against bacterial infections and recruitment of lymphocytes [6,7].

During pregnancy, the placenta undergoes structural changes to transfer maternal nutrients, oxygen, metabolites, and hormones to the fetus at different stages of development. These alterations are essential for the development and growth of the fetus [9,11,12]. One such change that occurs in early pregnancy is that the diameter of maternal blood vessels increases to supply a massive amount of maternal blood through the placenta at a low blood pressure. This phenomenon is called spiral artery remodeling, which is an essential change in the development of the placenta. During spiral artery remodeling, fetal origin trophoblasts invade maternal spiral arteries and replace endothelial cells undergoing apoptosis [12,13]. Apoptotic cells and debris are eliminated by placental macrophages and uterine natural killer (uNK) cells [12,13]. Rapid removal of apoptotic cells and debris is important for spiral artery remodeling. Inhibition of such removal hinders spiral blood vessel formation [12,13].

Stab1 and Stab2 proteins are expressed in endothelial cells and macrophages, which play a predominant role in artery remodeling in the placenta during pregnancy [12]. These proteins are closely related to factors mediating cell signaling pathways that regulate angiogenesis [4,9,14]. Functional studies of Stab1 and Stab2 in tissue macrophages have demonstrated their importance in the phagocytosis of apoptotic cells, suggesting that Stab1 and Stab2 contribute to placental reconstruction during pregnancy [1–3,10]. Interestingly, several studies have reported that Stab1 is expressed in placental endothelial cells and macrophages during pregnancy, and that it might be involved in cell adhesion and molecular scavenging in placental macrophages [1,3,9]. Previous studies have also suggested that Stab1 regulates differences in the concentration of mouse PL in maternal and fetal blood circulation [1,9]. However, the role of Stab1 in the placenta remains poorly understood and, to the best of our knowledge, the role of Stab2 in the placenta has not been reported yet.

In this study, we analyzed the mRNA expression levels of Stab1 and Stab2 in the placenta and compared them with those in the liver. In addition, we generated a double-knockout mouse strain lacking both Stab1 and Stab2 (Stab1/2 dKO mice) and observed defective reproduction in pregnant Stab1/2 dKO female mice. Furthermore, to determine the causes underlying these reproductive defects, we conducted a descriptive study to phenotypically characterize reproduction and placentation in pregnant Stab1/2 dKO female mice. This study provides the first description of Stab1/2 dKO affecting reproductive capacity and placental development, suggesting that Stab1 and Stab2 play an important role in placental reconstruction and remodeling during pregnancy.
