Uterine Vasculature Remodeling in Human Pregnancy Involves Functional Macrochimerism by Endothelial Colony Forming Cells of Fetal Origin

Abstract

The potency of adult-derived circulating progenitor endothelial colony forming cells (ECFCs) is drastically surpassed by their fetal counterparts. Human pregnancy is associated with robust intensification of blood flow and vascular expansion in the uterus, crucial for placental perfusion and fetal supply. Here, we investigate whether fetal ECFCs transmigrate to maternal bloodstream and home to locations of maternal vasculogenesis, primarily the pregnant uterus. In the first instance, endothelial-like cells, originating from mouse fetuses expressing paternal eGFP, were identified within uterine endothelia. Subsequently, LacZ or enhanced green fluorescent protein (eGFP)-labeled human fetal ECFCs, transplanted into immunodeficient (NOD/SCID) fetuses on D15.5 pregnancy, showed similar integration into the mouse uterus by term. Mature endothelial controls (human umbilical vein endothelial cells), similarly introduced, were unequivocally absent. In humans, SRY was detected in 6 of 12 myometrial microvessels obtained from women delivering male babies. The copy number was calculated at 175 [IQR 149–471] fetal cells per millimeter square endothelium, constituting 12.5% of maternal vessel lumina. Cross-sections of similar human vessels, hybridized for Y-chromosome, positively identified endothelial-associated fetal cells. It appears that through ECFC donation, fetuses assist maternal uterine vascular expansion in pregnancy, potentiating placental perfusion and consequently their own fetal supply. In addition to fetal growth, this cellular mechanism holds implications for materno-fetal immune interactions and long-term maternal vascular health.

Preeclampsia-Associated Alteration of DNA Methylation in Fetal Endothelial Progenitor Cells

“…An epigenetically modified endothelial precursor could affect both normal feto-placental vascular development and repair capacity and might influence the subsequent health of the offspring. Although implications for maternal pathogenesis of preeclampsia can not be inferred by our data, there is evidence that fetal ECFCs have a role in normal placental vasculogenesis and further that these cells traverse the placenta and home to sites of vessel formation in the maternal uterine microvasculature (Sipos et al, 2013).…”

Fluid shear stress regulates vascular remodeling via VEGFR-3 activation, although independently of its ligand, VEGF-C, in the uterus during pregnancy

“…The uterus is a special organ that experiences periodic vascular remodeling due to menstruation ( 8 , 10 , 11 ). The uterus exhibits marked neovascularization and vascular remodeling during early pregnancy, which promotes the stable development of the embryo ( 13 , 14 ). The failure of this process may be associated with pre-eclampsia, miscarriage and fetal growth restriction ( 25 , 27 ).…”

Fetal Microchimerism in Cancer Protection and Promotion: Current Understanding in Dogs and the Implications for Human Health

“…In the case of the female puppies, it is unknown if each was exposed to a different dose of male cells, whether the placental interface may be more or less permissive to cell transfer, or if fetal immune reactions to haplotype differences greatly impact the quantity of identifiable microchimeric cells [12]. A large exchange of maternal and fetal cells occurs in the creation of the uterine blood vessel network that sustains the pregnancy with 12% of uterine vessel endothelium deriving from the fetus [57]. This exchange of cells occurs against the backdrop of pregnancy-associated immune tolerance.…”

“…The presence of microchimerism in the recipient lowers the rate of rejection in humans receiving HLA-haploidentical renal transplants [60]. Human patients who are microchimeric and receive mismatched HSC transplant are more likely to engraft and have less graft vs host disease (GVHD) than patients who are not microchimeric [53][54][55][56][57][58][59][60][61].…”