Browsing by Author "Garretson, Rashell O."

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    Elevated transgelin reduces function of endothelial colony forming cells from gestational diabetic pregnancies
    (Office of the Vice Chancellor for Research, 2016-04-08) Varberg, Kaela M.; Garretson, Rashell O.; Blue, Emily K.; Haneline, Laura S.
    Fetal exposure to maternal diabetes predisposes children to future complications including hypertension and cardiovascular disease. A key mechanism by which these complications are thought to occur and persist is through the functional impairment of vascular progenitor cells, including endothelial colony forming cells (ECFCs). Previously, we showed that ECFCs exposed to gestational diabetes exhibit functional deficits, such as impaired vessel formation, but also differential gene expression compared to uncomplicated controls. One gene that was confirmed to be significantly upregulated in ECFCS from diabetic pregnancies was transgelin, an actin-binding smooth muscle protein. However, the functional consequences of increased transgelin in ECFCs are unknown. Therefore, to determine if transgelin is sufficient and required to induce dysfunction of ECFCs from diabetic pregnancies, transgelin protein levels were manipulated using genetic methods. Specifically, lentiviral overexpression and siRNA knockdown techniques were used in ECFCs from control and diabetic pregnancies respectively. Network formation assays and trans-well migration assays were performed to assess whether alteration of transgelin levels impact ECFC vasculogenesis and migration. Decreasing transgelin expression in diabetes-exposed ECFCs increased network formation (n=15, p<0.05) and cell migration (n=12, p<0.05). Conversely, overexpression of transgelin in ECFCs from uncomplicated pregnancies decreased network formation (n=12, p<0.05). Additional studies are underway to further elucidate intracellular signaling altered as a result of increased transgelin expression in diabetes-exposed ECFCs. Delineating the mechanisms underlying ECFC functional deficits will aid in the understanding of how and why chronic vascular complications persist in children born to mothers with diabetes.
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    Transgelin Induces Dysfunction of Fetal Endothelial Colony-Forming Cells From Gestational Diabetic Pregnancies
    (American Physiological Society, 2018-10-01) Varberg, Kaela M.; Garretson, Rashell O.; Blue, Emily K.; Chu, Chenghao; Gohn, Cassandra R.; Tu, Wanzhu; Haneline, Laura S.; Cellular and Integrative Physiology, School of Medicine
    Fetal exposure to gestational diabetes mellitus (GDM) predisposes children to future health complications including hypertension and cardiovascular disease. A key mechanism by which these complications occur is through the functional impairment of vascular progenitor cells, including endothelial colony-forming cells (ECFCs). Previously, we showed that fetal ECFCs exposed to GDM have decreased vasculogenic potential and altered gene expression. In this study, we evaluate whether transgelin (TAGLN), which is increased in GDM-exposed ECFCs, contributes to vasculogenic dysfunction. TAGLN is an actin-binding protein involved in the regulation of cytoskeletal rearrangement. We hypothesized that increased TAGLN expression in GDM-exposed fetal ECFCs decreases network formation by impairing cytoskeletal rearrangement resulting in reduced cell migration. To determine if TAGLN is required and/or sufficient to impair ECFC network formation, TAGLN was reduced and overexpressed in ECFCs from GDM and uncomplicated pregnancies, respectively. Decreasing TAGLN expression in GDM-exposed ECFCs improved network formation and stability as well as increased migration. In contrast, overexpressing TAGLN in ECFCs from uncomplicated pregnancies decreased network formation, network stability, migration, and alignment to laminar flow. Overall, these data suggest that increased TAGLN likely contributes to the vasculogenic dysfunction observed in GDM-exposed ECFCs, as it impairs ECFC migration, cell alignment, and network formation. Identifying the molecular mechanisms underlying fetal ECFC dysfunction following GDM exposure is key to ascertain mechanistically the basis for cardiovascular disease predisposition later in life.