Abstract
Purpose of Study: Diabetes Mellitus (DM) is the most prevalent risk factor for acquiring vascular disease. Since optimal glycemic control delays onset and progression of vascular morbidities, hyperglycemia is hypothesized to be a key pathogenic factor for vasculopathies. Vascular integrity requires endothelial repair and angiogenesis. Recently, circulating endothelial progenitor cells (EPCs) were shown to have a critical role in promoting endothelial repair and angiogenesis. Given that infants exposed to a diabetic intrauterine environment have an increased risk of DM and vascular disease, we hypothesize that hyperglycemia alters neonatal EPC function. Thus, our aims were to examine the effect of hyperglycemia on newborn EPC clonogenic capacity, proliferative potential, apoptosis, senescence, and capillary tube formation.
Methods Used: EPCs were isolated from multiple cord blood donors as described (Ingram et al, Blood, 104:2752, 2004) and subjected to euglycemia or hyperglycemia (10-100 mM dextrose) before conducting cellular and functional assays. Limiting dilution assays assessed EPC colony formation. Single cell assays quantitated the proportion of single EPCs capable of dividing. Proliferation potential was also assessed by population doubling studies. Apoptosis was evaluated using a TUNEL assay while senescence was examined using an acidic β-galactosidase method. Matrigel assays assessed capillary tube forming ability.
Summary of Results: Hyperglycemia (10-100 mM) resulted in reduced EPC colony formation compared to controls (n=3, p<0.05). Hyperglycemia led to decreased EPC proliferative potential as reflected by a decrease in the number of single EPC cells dividing (n=96 single cells) and a lower cumulative population doubling level. In addition, increased apoptosis was detected after a 24 or 48 hour exposure to high dextrose concentrations (50mM and 100mM) compared to controls (n=3, p< 0.003). Senescence assays are underway, and preliminary matrigel assays suggest that hyperglycemia treated EPCs exhibit reduced capillary tube formation.
Conclusion: These data demonstrate that neonatal EPCs have decreased clonogenic potential after hyperglycemia treatment. The mechanisms for the observed decrease in clonogenic capacity may include an increase in both apoptosis and senescence together with a decrease in proliferation. Collectively, these observations may have implications for the pathogenesis of vascular disease in diabetic patients as well as in infants exposed to a diabetic intrauterine environment.
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Lien, I., Dropcho, E., Mead, L. et al. 15 The Effects of Hyperglycemia on Newborn Endothelial Progenitor Cells.. Pediatr Res 60, 493 (2006). https://doi.org/10.1203/00006450-200610000-00037
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DOI: https://doi.org/10.1203/00006450-200610000-00037
