The Effect of Carbon Monoxide on Pregnancy Specific Adaptations in Mice
Preeclampsia (PE) is a multisystem disorder of pregnancy, characterized by new onset hypertension and the presence of specific organ dysfunction such as proteinuria. While the etiology remains elusive, it is believed to be a disease of placental origin. Carbon monoxide (CO) is actively being studied as a potential therapeutic for PE due to its vasodilatory, angiogenic, and anti-inflammatory properties, with the aim that CO can improve placental function and maternal vascular dysfunction during pregnancy. CO has been shown to increase uteroplacental vascular growth and prevent PE-like signs in mice. How CO acts to promote vascular changes during pregnancy is unclear. Thus, the objectives of this research were to determine the effect of low-dose CO on markers of angiogenesis and inflammation at both the maternal-fetal interface and systemically during mouse pregnancy, and to characterize the effect of CO on histomorphological changes at the implantation site. The hypothesis that CO increases angiogenesis during pregnancy via modulation of major angiogenic/inflammatory pathways was tested using healthy, pregnant CD-1 mice. Following chronic administration of 250 ppm CO, genes encoding VEGF and angiopoietin receptors, eNOS, and cell adhesion molecules were upregulated at the implantation sites at gestation day (GD)10.5; no changes in gene expression were observed at GD16.5. Furthermore, CO treatment did not reveal any measurable changes in pro-inflammatory or angiogenic cytokines in the plasma or tissue lysates from implantation sites. Additionally, histological analysis at GD10.5 and GD16.5 implantation sites demonstrated no difference in cell markers characteristic of placental health and function, including trophoblast invasion (pan-cytokeratin), cellular proliferation (Ki67), and uterine natural killer cell abundance (Dolichos biflorus lectin). Collectively, the data presented in this thesis suggest that CO acts to potentiate uteroplacental vascular growth via the angiogenic axis at midgestation, without impacting pregnancy specific adaptations including local/systemic immune function and histomorphological changes at the maternal-fetal interface. Understanding how low-dose CO modulates angiogenesis and inflammation during normal pregnancy is crucial prior to its use therapeutically. Future studies are required to validate the safety and efficacy of CO as a potential therapeutic for vascular insufficiency diseases such as PE.