Physiological Transformation of the Uterine Spiral Arteries During Human Pregnancy: Growth Factors Released by Uterine Natural Killer Cells Initiate Vascular Remodeling.

During the first twenty weeks of human pregnancy, the uterine spiral arteries are progressively remodeled to form dilated channels lacking maternal vasomotor control. This process ensures that maternal blood is delivered to the developing placenta at an optimal rate for nutrient exchange. The initial stages of spiral artery remodeling are characterized by dissociation and disruption of vascular smooth muscle cell (VSMC) layers, which is coincident with an influx of uterine natural killer (uNK) cells into the vessel wall. Subsequently, extravillous trophoblast cells (EVT) derived from the placenta colonize the spiral arteries and replace the vascular cells. Using an ex vivo culture model, we have previously shown that conditioned medium collected from human first trimester uNK cells induces disorganization and dedifferentiation of VSMC in isolated spiral arteries obtained from non-pregnant women. We therefore hypothesized that soluble factors released by uNK cells could initiate disruption of vessel wall architecture and degradation of the vascular extracellular matrix (ECM). To identify the growth factors involved, we obtained myometrial biopsies from non-pregnant, pre-menopausal women undergoing hysterectomy and dissected out the spiral arteries. Arteries were cultured with growth factors (10ng/ml) known to be produced by uNK cells during pregnancy, including recombinant human interferon gamma (rhIFN-gamma), vascular endothelial cell growth factor-C (VEGF-C), angiopoietin 1 (Ang-1) or angiopoietin-2 (Ang-2) for 72h, in the presence or absence of function blocking antibodies (1-2 µg/ml). Transverse sections of frozen arteries were stained with propidium iodide and were scored for evidence of VSMC misalignment, separation of VSMC layers and rounding of VSMC nuclei. rhAng-1 and Ang-2 significantly increased VSMC misalignment, separation of VSMC layers and rounding of VSMC nuclei (*P<0.05, n=5-6, Kruskal-Wallis test); these effects were reversed following the inclusion of a function blocking antibody. VEGF-C also modestly enhanced VSMC misalignment and rounding of VSMC nuclei, but did not induce separation of VSMC layers (*P<0.05, n=6). Interferon-gamma induced significant rounding of VSMC nuclei (*P<0.05, n=5), but did not alter other parameters of vascular disruption. To investigate whether uNK cell-derived factors can initiate breakdown of the vascular ECM, spiral arteries were cultured with uNK cell-conditioned medium (uNK-CM) for 72h and stained with antibodies to collagen IV, laminin, and elastin. A marked reduction in immunoreactivity of each molecule was observed, along with the loss of discrete ECM layers, suggesting that uNK cell-derived factors can degrade the vascular ECM. Addition of a broad spectrum matrix metalloproteinase (MMP) inhibitor (NNGH; 50microM) to the uNK-CM abrogated the effect, implying that uNK-derived proteases catabolize the vascular ECM. Indeed, VSMC misalignment, separation of VSMC layers and rounding of VSMC nuclei were all significantly inhibited following MMP inhibition (*P<0.05, n=6). These data demonstrate that uNK cells are key regulators of spiral artery remodeling in human pregnancy, producing factors that disrupt VSMC interactions and initiate ECM catabolism, priming the arteries for subsequent colonization by EVT. This research was supported by the BBSRC, UK. (platform)

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