Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets

doi:10.1016/j.ajog.2010.10.913

American Journal of Obstetrics and Gynecology

Volume 204, Issue 3, March 2011, Pages 254.e8-254.e15

Presented in part at the Society for Pediatric Academic Societies Meeting, Honolulu, HI, May 5, 2008.

https://doi.org/10.1016/j.ajog.2010.10.913 Get rights and content

Objective

The purpose of this study was to examine whether women with gestational diabetes mellitus (GDM) and their offspring have reduced endothelial progenitor cell subsets and vascular reactivity.

Study Design

Women with GDM, healthy control subjects, and their infants participated. Maternal blood and cord blood were assessed for colony-forming unit–endothelial cells and endothelial progenitor cell subsets with the use of polychromatic flow cytometry. Cord blood endothelial colony-forming cells were enumerated. Vascular reactivity was tested by laser Doppler imaging.

Results

Women with GDM had fewer CD34, CD133, CD45, and CD31 cells (circulating progenitor cells [CPCs]) at 24-32 weeks' gestation and 1-2 days after delivery, compared with control subjects. No differences were detected in colony-forming unit–endothelial cells or colony-forming unit–endothelial cells. In control subjects, CPCs were higher in the third trimester, compared with the postpartum period. Cord blood from GDM pregnancies had reduced CPCs. Vascular reactivity was not different between GDM and control subjects.

Conclusion

The normal physiologic increase in CPCs during pregnancy is impaired in women with GDM, which may contribute to endothelial dysfunction and GDM-associated morbidities.

Section snippets

Materials and Methods

Women with GDM and healthy pregnant control subjects were recruited through obstetric clinics and advertisements. Women were studied from 24-32 weeks' gestation according to the obstetricians' best estimate of gestation, 1-2 postpartum days, and 6-8 postpartum weeks. Newborn infants were studied at 1-2 days of age. GDM was defined according to the American College of Obstetrics and Gynecology guidelines. Exclusion criteria included type 1 or 2 diabetes mellitus; illnesses known to affect

Results

Forty-six pregnant women were enrolled; 27 women with GDM and 19 control subjects with a normal GDM screening test. Control subjects had no history of GDM and were not taking any prescription medications. One control subject had a diagnosis of hypertriglyceridemia and smoked tobacco. Of the GDM group, 2 women had GDM with a previous pregnancy; 1 woman smoked tobacco, and 1 woman was on sertraline for depression. Age, parity, blood pressure, and prepregnancy BMI, based on self-reported weight,

Comment

Here, we demonstrate that CPCs are reduced in women with GDM, compared with pregnant control subjects, during the third trimester and early postpartum period. Additionally, in uncomplicated pregnancies, CPCs are higher in the third trimester, compared with 1-2 days and 6-8 weeks after delivery. Interestingly, CPCs in control subjects at 1-2 days after delivery approach levels that have been detected in nonpregnant individuals,13, 14 which suggests a quick return to baseline after delivery. Our

Acknowledgments

We thank research nurses Lucy Miller and Tammy Garrett and obstetric diabetes dietitian Barbara Amerman for assisting with protocol implementation; Dr Sandra Hoesli (Vanderbilt University) for assistance with laser Doppler imaging, and the Angiogenesis and Endothelial Progenitor Cell Core, which is run by Dr Jamie Case with analyses conducted by Myka Estes and Julie Mund.

References (30)

M.D. Savvidou et al.
Maternal circulating endothelial progenitor cells in normal singleton and twin pregnancy
Am J Obstet Gynecol
(2008)
M.C. Yoder et al.
Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals
Blood
(2007)
L.A. Dimeglio et al.
Endothelial abnormalities in adolescents with type 1 diabetes: a biomarker for vascular sequelae
J Pediatr
(2010)
H.S. Hwang et al.
Increased senescence and reduced functional ability of fetal endothelial progenitor cells in pregnancies complicated by preeclampsia without intrauterine growth restriction
Am J Obstet Gynecol
(2008)
M. Buemi et al.
Concentration of circulating endothelial progenitor cells (EPC) in normal pregnancy and in pregnant women with diabetes and hypertension
Am J Obstet Gynecol
(2007)
H. Guven et al.
The number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary artery disease
J Am Coll Cardiol
(2006)
N.H. Cho et al.
Correlations between the intrauterine metabolic environment and blood pressure in adolescent offspring of diabetic mothers
J Pediatr
(2000)
M. Vasa et al.
Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease
Circ Res
(2001)
G.P. Fadini et al.
Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy
Arterioscler Thromb Vasc Biol
(2006)
J.M. Hill et al.
Circulating endothelial progenitor cells, vascular function, and cardiovascular risk
N Engl J Med
(2003)

A.O. Robb et al.

Endothelial progenitor cells in pregnancy

Reproduction

(2007)

H.S. Gammill et al.

Endothelial progenitor cells and preeclampsia

Front Biosci

(2007)

J. Sugawara et al.

Decrease and senescence of endothelial progenitor cells in patients with preeclampsia

J Clin Endocrinol Metab

(2005)

J. Sugawara et al.

Circulating endothelial progenitor cells during human pregnancy

J Clin Endocrinol Metab

(2005)

C. Lin et al.

Maternal endothelial progenitor colony-forming units with macrophage characteristics are reduced in preeclampsia

Am J Hypertens

(2009)

Cited by (35)

Exosome enriched leucine-rich alpha-2-glycoprotein-1 and extracellular matrix protein 1 proteins induce abnormal placental angiogenesis in pregnant mice
2023, Placenta
Gestational Diabetes Mellitus (GDM) is characterized by a high risk of fetal macrosomia and placenta hypervascularization. Exosomes has been known participating in various physiological and pathological processes, including pro-angiogenic function. However, the effects of umbilical cord blood derived exosomes from cases of GDM (GDM-exo) on placental vascular network formation remain unclear.
In the current study, we isolated and identified exosomes in umbilical cord blood from both normal (N-exo) and GDM pregnancies. Meanwhile, we investigated the effects of umbilical cord blood derived exosomes on placental angiogenesis both in vitro and in vivo.
Our data indicated that in a mouse model, the placenta and fetus weight were significantly higher in the ones administrated with GDM-exo when compared with N-exo. Meanwhile, GDM-exo significantly enhanced placental endothelial cells functions in both HUVEC and HPMEC endothelial cell models. Importantly, we explored two up-regulated proteins in GDM-exo, namely leucine-rich alpha-2-glycoprotein-1 (LRG1) and extracellular matrix protein 1 (ECM1) by proteome analysis, which performed largely pro-angiogenic function and probably resulted in hypervascularization in GDM placenta.
Thus, we proposed that abundant LRG1 and ECM1 enriched GDM-exo may take important roles in regulating pathological placental angiogenesis.
Recent advances in antenatal factors predisposing to bronchopulmonary dysplasia
2018, Seminars in Perinatology
Citation Excerpt :
Hyperoxia decreases nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) and VEGF receptor-2 (VEGFR-2) protein expression ex vivo, an effect that is mimicked by NOS inhibition.55 The inhibitory growth effect of hyperoxia was mitigated by treatment with NO or VEGF (with increased eNOS expression), and antioxidant therapies.52,56 Fetal oxidative stress is inversely related to GA (assessed by cord 8-isoprostane levels at birth), resulting in additional vulnerability for the most preterm infants.56
Bronchopulmonary dysplasia (BPD) remains a major cause of late morbidities and death after preterm birth. BPD is characterized by an arrest of vascular and alveolar growth and high risk for pulmonary hypertension; yet mechanisms contributing to its pathogenesis and early strategies to prevent BPD are poorly understood. Strong epidemiologic studies have shown that the “new BPD” reflects the long-lasting impact of antenatal factors on lung development, partly due to placental dysfunction, as reflected in recent data from animal models. Improved understanding of mechanisms through which antenatal stress alters placental function and contributes to BPD may lead to preventive therapies.
Vitamin D rescues dysfunction of fetal endothelial colony forming cells from individuals with gestational diabetes
2015, Placenta
Citation Excerpt :
Factors not determined in our study, e.g. placental factors, could impact ECFC function in GDM patients. Our results are consistent with other reports of fetal ECFC function in a diabetic or hyperglycemic environment [27–30]. To our knowledge, however, we are the first to show that vitamin D improves ECFC function even under gestational diabetic conditions.
Gestational diabetes (GDM) is associated with long-term cardiovascular and metabolic diseases in offspring. However, the mechanisms are not well understood. We explored whether fetal exposure to a diabetic environment is associated with fetal endothelial progenitor cell dysfunction, and whether vitamin D can reverse the impairment.
Nineteen women with uncomplicated pregnancies and 18 women with GDM were recruited before delivery. Time to first appearance of endothelial colony forming cell (ECFC) colonies and number of ECFC colonies formed from culture of cord peripheral blood mononuclear cells were determined. Angiogenesis-related functions of ECFCs in vitro were tested in the presence or absence of vitamin D.
Fetal ECFCs from GDM pregnancies formed fewer colonies in culture (P = 0.04) and displayed reduced proliferation (P = 0.02), migration (P = 0.04) and tubule formation (P = 0.03) compared to uncomplicated pregnancies. Fetal ECFCs exposed to hyperglycemia in vitro exhibited less migration (P < 0.05) and less tubule formation (P < 0.05) than normoglycemic control. Vitamin D significantly improved the dysfunction of fetal ECFCs from pregnancies complicated by GDM or after exposure of healthy ECFCs to hyperglycemia.
Fetal ECFCs from GDM pregnancies or ECFCs exposed to hyperglycemia in vitro exhibit reduced quantity and impaired angiogenesis-related functions. Vitamin D significantly rescues these functions. These findings may have implications for vascular function of infants exposed to a diabetic intrauterine environment.
Maternal body-mass index and cord blood circulating endothelial colony-forming cells
2014, Journal of Pediatrics
Citation Excerpt :
The main implication of this study is the need to consider maternal BMI as a potential confounding factor for cord blood levels of ECFCs. Emerging evidence indicates that deleterious conditions during fetal life can impair ECFC content and function,10-12,22 and the level of these cells may vary extensively. Understanding what constitutes a normal baseline level of ECFC abundance will facilitate the interpretation of future comparative studies between pathologic and non-pathologic pregnancies.
Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that are particularly abundant in umbilical cord blood. We sought to determine whether ECFC abundance in cord blood is associated with maternal body-mass index (BMI) in nonpathologic pregnancies.
We measured the level of ECFCs in the cord blood of neonates (n = 27) born from non-obese healthy mothers with nonpathologic pregnancies and examined whether ECFC abundance correlated with maternal BMI. We also examined the effect of maternal BMI on ECFC phenotype and function using angiogenic and vasculogenic assays.
We observed variation in ECFC abundance among subjects and found a positive correlation between prepregnancy maternal BMI and ECFC content (r = 0.51, P = .007), which was independent of other obstetric factors. Despite this variation, ECFC phenotype and functionality were deemed normal and highly similar between subjects with maternal BMI <25 kg/m² and BMI between 25-30 kg/m², including the ability to form vascular networks in vivo.
This study underlines the need to consider maternal BMI as a potential confounding factor for cord blood levels of ECFCs in future comparative studies between healthy and pathologic pregnancies.
The diagnostic criteria for gestational diabetes: To change or not to change?
2013, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Research suggests, however, that maternal gestational hyperglycemia and subsequent fetal hyperinsulinemia may predispose offspring to increased adiposity, impaired glucose tolerance, hyperinsulinemia, and insulin resistance.25 Women with GDM also have been shown to have fewer circulating progenitor cells at 24-32 weeks' gestation and 1-2 days postpartum compared to controls.26 Because the normal physiologic increase in circulating progenitor cells during pregnancy is impaired in women with GDM, it is believe that this impairment may contribute to endothelial dysfunction and GDM-associated morbidities in mothers and infants.
The different screening and diagnostic methods for gestational diabetes mellitus (GDM) currently in clinical use have led the National Institutes of Health Office of Disease Prevention to organize a consensus conference to better understand the potential ramifications of changing the current screening and diagnostic criteria in the United States vs keeping current practices in place. Research has demonstrated that even mild forms of hyperglycemia potentially pose significant adverse health consequences for pregnant women and their children. Thus, it is anticipated that lowering the diagnostic criteria for GDM will significantly reduce morbidity and health care costs in the long term. However, such a change would dramatically increase the number of women identified as having this disease and place a significantly greater burden on an already overburdened primary health care system. Although several cost-benefit analyses suggest that such a change will improve health outcomes for mothers and babies, at least 1 study found that these anticipated public health benefits will not occur unless a higher level of care is devoted to these newly diagnosed patients. There also is a distinct possibility that changing the diagnostic criteria for GDM will increase cesarean delivery rates, which might offset many of the public health gains engendered by diagnosing more women with this condition. The scientific dilemma to change or not to change, thus, requires a rigorous analysis of the scientific, economic, practice, and legal pros and cons to achieve a satisfactory answer.
Implications of maternal-fetal health on perinatal stem cell banking
2024, Gene Therapy

View all citing articles on Scopus

: Supported by US Public Health Services Grants R21 HL08885 (D.A.I., L.S.H.), R01 HL094725 (D.A.I., L.S.H.), P30 CA82709 (D.A.I., L.S.H.), UL1 RR025761 (C.K.S., L.A.D., D.A.I), U10HD063094 (D.M.H., L.S.H.), and the Riley Children's Foundation (D.A.I., L.S.H.).

: Cite this article as: Acosta JC, Haas DM, Saha CK, et al. Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets. Am J Obstet Gynecol 2011;204:••••.

View full text

ResearchBasic science: ObstetricsGestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets

Objective

Study Design

Results

Conclusion

Section snippets

Materials and Methods

Results

Comment

Acknowledgments

Am J Obstet Gynecol

Blood

J Pediatr

Am J Obstet Gynecol

Am J Obstet Gynecol

J Am Coll Cardiol

J Pediatr

Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease

Circ Res

Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy

Arterioscler Thromb Vasc Biol

Circulating endothelial progenitor cells, vascular function, and cardiovascular risk

N Engl J Med

Endothelial progenitor cells in pregnancy

Reproduction

Endothelial progenitor cells and preeclampsia

Front Biosci

Decrease and senescence of endothelial progenitor cells in patients with preeclampsia

J Clin Endocrinol Metab

Circulating endothelial progenitor cells during human pregnancy

J Clin Endocrinol Metab

Maternal endothelial progenitor colony-forming units with macrophage characteristics are reduced in preeclampsia

Am J Hypertens

Research
Basic science: Obstetrics
Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets