Significant evidence demonstrates that an adverse in utero environment increases offspring risk for vascular disease. While initial reports focused on growth restricted infants, data suggest that maternal diabetes (DM) predisposes offspring to vascular disease. Together these data suggest that the fetal vasculature is highly susceptible to injury. A critical component of vascular health is intact endothelial function. Homeostatic regulation of the endothelium requires dynamic interactions between endothelial cells and cells circulating in the blood to sustain endothelial function. Importantly, endothelial progenitor cells (EPCs) orchestrate vascular repair and vessel formation. Additionally, numerous studies in adults demonstrate a correlation between reduced peripheral blood EPC numbers and function with increased vascular disease risk. However, no studies have examined whether a similar correlation exists in children. Together these data form the basis for our overall hypothesis. We hypothesize that a maternal type 2 DM (T2DM) intrauterine environment subjects the fetus to significant stress resulting in decreased EPC numbers, loss of EPC functional capacity, and increased risk for endothelial dysfunction in offspring. EPC subpopulations can be identified by culture methods and flow cytometry. Two EPC subpopulations with distinct functional properties have been reported. However, few studies have evaluated the function of these EPCs from pediatric subjects, despite data indicating that both EPC types are operative in vascular repair. Studies outlined in this application will directly interrogate whether dysfunction of both EPC subpopulations are involved in endothelial dysfunction of offspring from T2DM pregnancies and examine the contribution of premature aging in the functional capacity of EPCs. Elucidating the underlying mechanisms responsible for the increased risk of vascular disease in offspring of T2DM mothers is paramount to finding potential preventative strategies. Further, pediatric studies offer the potential to identify biomarkers of vascular disease risk such that early interventions may be implemented to disrupt this pathology.

Public Health Relevance

In this application, we will directly interrogate whether dysfunction of endothelial progenitor cells are involved in endothelial dysfunction of offspring from mothers with type 2 diabetes. Elucidating the underlying mechanisms responsible for the increased risk of vascular disease in offspring of type 2 diabetic mothers is paramount to finding potential preventative strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094725-02
Application #
7901560
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Pemberton, Victoria
Project Start
2009-08-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$366,227
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Varberg, Kaela M; Winfree, Seth; Dunn, Kenneth W et al. (2018) Kinetic Analysis of Vasculogenesis Quantifies Dynamics of Vasculogenesis and Angiogenesis In Vitro. J Vis Exp :
Gohn, Cassandra R; Blue, Emily K; Sheehan, BreAnn M et al. (2017) Mesenchyme Homeobox 2 Enhances Migration of Endothelial Colony Forming Cells Exposed to Intrauterine Diabetes Mellitus. J Cell Physiol 232:1885-1892
Blue, Emily K; Sheehan, BreAnn M; Nuss, Zia V et al. (2015) Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus. Diabetes 64:2664-75
Blue, Emily K; DiGiuseppe, Robert; Derr-Yellin, Ethel et al. (2014) Gestational diabetes induces alterations in the function of neonatal endothelial colony-forming cells. Pediatr Res 75:266-72
Acosta, Juan C; Haas, David M; Saha, Chandan K et al. (2011) Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets. Am J Obstet Gynecol 204:254.e8-254.e15