Indiana University-Purdue University Indianapolis (IUPUI) / In the United States, 10% of pregnancies are complicated by diabetes
mellitus (DM). Intrauterine DM exposure can have long-lasting implications for
the fetus, including cardiovascular morbidity. Previously, we showed that fetal
endothelial colony forming cells (ECFCs) from DM pregnancies have decreased
vessel-forming ability and increased senescence. However, the molecular
mechanisms responsible for this dysfunction remain largely unknown. The
objective of this thesis was to understand how Mesenchyme Homeobox 2
(MEOX2) interacts with pathways that regulate cell cycle progression and
migration, and how this interaction results in impaired vasculogenesis in DM
exposed ECFCs.
We tested the hypothesis that upregulated MEOX2 in DM-exposed
ECFCs decreases network formation through impairments in senescence, cell
cycle progression, migration, and adhesion. MEOX2 is a transcription factor
which inhibits angiogenesis by upregulating cyclin dependent kinase inhibitors.
Here, data show that nuclear MEOX2 is increased in DM-exposed ECFCs.
Lentiviral-mediated overexpression of MEOX2 in control ECFCs increased
network formation, altered cell cycle progression, increased senescence, and
enhanced migration. In contrast, MEOX2-knockdown in DM-exposed ECFCs decreased network formation and migration, while cell cycle progression and
senescence were unchanged.
Adhesion and integrin expression defects were evaluated as mechanisms
by which MEOX2 altered ECFC migration. While MEOX2-overexpression did not
alter adhesion or cell surface integrin levels in control cells, MEOX2
overexpression in DM-exposed ECFCs resulted in an increase in α6 integrin
surface expression. Similarly, MEOX2-knockdown in DM-exposed ECFCs did not
alter adhesion, though did reduce α6 integrin surface expression and total
cellular α6 mRNA and protein levels.
Together, these data suggest that alterations in cell cycle progression and
senescence are not responsible for the disrupted vasculogenesis of DM-exposed
ECFCs. Importantly, these data suggest that altered migration may be a key
mechanism involved and that altered cell surface levels of the α6 integrin may
modify migratory capacity. Moreover, these data suggest that the α6 integrin may
be a previously unrecognized transcriptional target of MEOX2. Ultimately, while
initially believed to be maladaptive, these data suggest that increased nuclear
MEOX2 in DM-exposed ECFCs may serve a protective role, enabling vessel
formation despite exposure to a DM intrauterine environment.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/13846 |
| Date | 19 June 2017 |
| Creators | Gohn, Cassandra Rebekah |
| Contributors | Haneline, Laura S., Elmendorf, Jeffrey S., Herring, B. Paul, Tune, Johnathan D. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
Page generated in 0.0024 seconds