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Vitamin D antagonizes negative effects of preeclampsia on fetal endothelial colony forming cell number and function.

von Versen-Höynck F, Brodowski L, Dechend R, Myerski AC, Hubel CA - PLoS ONE (2014)

Bottom Line: VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3.Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional.Vitamin D3 had rescuing effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Gynecology Research Unit, Hannover Medical School, Hannover, Germany.

ABSTRACT

Context: Endothelial dysfunction is a primary feature of preeclampsia, a pregnancy complication associated with an increased future cardiovascular risk for mother and offspring. Endothelial colony forming cells (ECFC) are endothelial progenitor cells that participate in vasculogenesis and endothelial repair.

Objective: We hypothesized that the number and functional properties of fetal cord blood-derived ECFCs are reduced in preeclampsia compared to uncomplicated pregnancy (controls), and asked if adverse effects of preeclampsia on ECFC function are reversed by 1,25 (OH)2 vitamin D3.

Design, setting, patients: This was a nested, case-control study. Forty women with uncomplicated pregnancy and 33 women with PE were recruited at Magee-Womens Hospital (USA) or at Hannover Medical School (Germany).

Main outcome measures: Time to ECFC colony appearance in culture, and number of colonies formed, were determined. Functional abilities of ECFCs were assessed in vitro by tubule formation in Matrigel assay, migration, and proliferation. ECFC function was tested in the presence or absence of 1,25 (OH)2 vitamin D3, and after vitamin D receptor (VDR) or VEGF signaling blockade.

Results: The number of cord ECFC colonies was lower (P = 0.04) in preeclampsia compared to controls. ECFCs from preeclampsia showed reduced proliferation (P<0.0001), formed fewer tubules (P = 0.02), and migrated less (P = 0.049) than control. Vitamin D3 significantly improved preeclampsia ECFC functional properties. VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3.

Conclusion: Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional. Vitamin D3 had rescuing effects. This may have implications for the increased cardiovascular risk associated with preeclampsia.

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Related in: MedlinePlus

Effect of 1,25(OH)2 vitamin D3 and the inhibitors pyridoxal-5-phosphate, SU5416 and vitamin D receptor (VDR) small interfering (si)RNA on capillary-tube formation.ECFCs of uncomplicated (control) and preeclamptic (PE) pregnancies were cultured in EBM +5% (v/v) FBS and treated with 10 nM 1,25(OH)2 vitamin D3 for 14 h. Control: uncomplicated pregnancy. PE: pregnancy complicated by preeclampsia. Capillary-tube formation was determined by seeding 17,000 ECFCs on 50 µl Matrigel and incubated with 0.5 mM pyridoxal-5-phophate, 0.5 µM SU5416 (A) or 50 nM VDR siRNA or non-targeting siRNA (B) each either without additional 1,25(OH)2 vitamin D3 or with 10 nM 1,25(OH)2 vitamin D3 treatment respectively. Tubule length was analyzed after 14 h by visual microscopy at 2.5× magnification. Results represent mean ±SEM of at least 4 independent experiments. *P<0.05 compared to control.
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pone-0098990-g004: Effect of 1,25(OH)2 vitamin D3 and the inhibitors pyridoxal-5-phosphate, SU5416 and vitamin D receptor (VDR) small interfering (si)RNA on capillary-tube formation.ECFCs of uncomplicated (control) and preeclamptic (PE) pregnancies were cultured in EBM +5% (v/v) FBS and treated with 10 nM 1,25(OH)2 vitamin D3 for 14 h. Control: uncomplicated pregnancy. PE: pregnancy complicated by preeclampsia. Capillary-tube formation was determined by seeding 17,000 ECFCs on 50 µl Matrigel and incubated with 0.5 mM pyridoxal-5-phophate, 0.5 µM SU5416 (A) or 50 nM VDR siRNA or non-targeting siRNA (B) each either without additional 1,25(OH)2 vitamin D3 or with 10 nM 1,25(OH)2 vitamin D3 treatment respectively. Tubule length was analyzed after 14 h by visual microscopy at 2.5× magnification. Results represent mean ±SEM of at least 4 independent experiments. *P<0.05 compared to control.

Mentions: We silenced the VDR with siRNA or blocked the VDR with the VDR antagonist pyridoxal-5-phosphate (P5P). To test whether VEGF signaling could be involved, we pre-treated cells with the Flk-1/KDR (VEGF) receptor tyrosine kinase inhibitor SU5416. Tubule lengths per microscopic field in Figure 4 are expressed as percentage relative to values from untreated, uncomplicated pregnancy ECFCs, with experiments performed in the presence of 5% (v/v) FBS. As shown in Figure 4 A, tubule formation by PE ECFCs was lower than uncomplicated pregnancy ECFCs in the absence of vitamin D (76±13, P = 0.08, n = 4). Treatment with 10 nM vitamin D increased tubule formation in both groups (uncomplicated pregnancy: 108±2, P = 0.03, n = 5; PE: 114±3, P = 0.02, n = 4, (data expressed as percent relative to vitamin D-untreated uncomplicated pregnancy or PE ECFCs, respectively).


Vitamin D antagonizes negative effects of preeclampsia on fetal endothelial colony forming cell number and function.

von Versen-Höynck F, Brodowski L, Dechend R, Myerski AC, Hubel CA - PLoS ONE (2014)

Effect of 1,25(OH)2 vitamin D3 and the inhibitors pyridoxal-5-phosphate, SU5416 and vitamin D receptor (VDR) small interfering (si)RNA on capillary-tube formation.ECFCs of uncomplicated (control) and preeclamptic (PE) pregnancies were cultured in EBM +5% (v/v) FBS and treated with 10 nM 1,25(OH)2 vitamin D3 for 14 h. Control: uncomplicated pregnancy. PE: pregnancy complicated by preeclampsia. Capillary-tube formation was determined by seeding 17,000 ECFCs on 50 µl Matrigel and incubated with 0.5 mM pyridoxal-5-phophate, 0.5 µM SU5416 (A) or 50 nM VDR siRNA or non-targeting siRNA (B) each either without additional 1,25(OH)2 vitamin D3 or with 10 nM 1,25(OH)2 vitamin D3 treatment respectively. Tubule length was analyzed after 14 h by visual microscopy at 2.5× magnification. Results represent mean ±SEM of at least 4 independent experiments. *P<0.05 compared to control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4044051&req=5

pone-0098990-g004: Effect of 1,25(OH)2 vitamin D3 and the inhibitors pyridoxal-5-phosphate, SU5416 and vitamin D receptor (VDR) small interfering (si)RNA on capillary-tube formation.ECFCs of uncomplicated (control) and preeclamptic (PE) pregnancies were cultured in EBM +5% (v/v) FBS and treated with 10 nM 1,25(OH)2 vitamin D3 for 14 h. Control: uncomplicated pregnancy. PE: pregnancy complicated by preeclampsia. Capillary-tube formation was determined by seeding 17,000 ECFCs on 50 µl Matrigel and incubated with 0.5 mM pyridoxal-5-phophate, 0.5 µM SU5416 (A) or 50 nM VDR siRNA or non-targeting siRNA (B) each either without additional 1,25(OH)2 vitamin D3 or with 10 nM 1,25(OH)2 vitamin D3 treatment respectively. Tubule length was analyzed after 14 h by visual microscopy at 2.5× magnification. Results represent mean ±SEM of at least 4 independent experiments. *P<0.05 compared to control.
Mentions: We silenced the VDR with siRNA or blocked the VDR with the VDR antagonist pyridoxal-5-phosphate (P5P). To test whether VEGF signaling could be involved, we pre-treated cells with the Flk-1/KDR (VEGF) receptor tyrosine kinase inhibitor SU5416. Tubule lengths per microscopic field in Figure 4 are expressed as percentage relative to values from untreated, uncomplicated pregnancy ECFCs, with experiments performed in the presence of 5% (v/v) FBS. As shown in Figure 4 A, tubule formation by PE ECFCs was lower than uncomplicated pregnancy ECFCs in the absence of vitamin D (76±13, P = 0.08, n = 4). Treatment with 10 nM vitamin D increased tubule formation in both groups (uncomplicated pregnancy: 108±2, P = 0.03, n = 5; PE: 114±3, P = 0.02, n = 4, (data expressed as percent relative to vitamin D-untreated uncomplicated pregnancy or PE ECFCs, respectively).

Bottom Line: VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3.Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional.Vitamin D3 had rescuing effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Gynecology Research Unit, Hannover Medical School, Hannover, Germany.

ABSTRACT

Context: Endothelial dysfunction is a primary feature of preeclampsia, a pregnancy complication associated with an increased future cardiovascular risk for mother and offspring. Endothelial colony forming cells (ECFC) are endothelial progenitor cells that participate in vasculogenesis and endothelial repair.

Objective: We hypothesized that the number and functional properties of fetal cord blood-derived ECFCs are reduced in preeclampsia compared to uncomplicated pregnancy (controls), and asked if adverse effects of preeclampsia on ECFC function are reversed by 1,25 (OH)2 vitamin D3.

Design, setting, patients: This was a nested, case-control study. Forty women with uncomplicated pregnancy and 33 women with PE were recruited at Magee-Womens Hospital (USA) or at Hannover Medical School (Germany).

Main outcome measures: Time to ECFC colony appearance in culture, and number of colonies formed, were determined. Functional abilities of ECFCs were assessed in vitro by tubule formation in Matrigel assay, migration, and proliferation. ECFC function was tested in the presence or absence of 1,25 (OH)2 vitamin D3, and after vitamin D receptor (VDR) or VEGF signaling blockade.

Results: The number of cord ECFC colonies was lower (P = 0.04) in preeclampsia compared to controls. ECFCs from preeclampsia showed reduced proliferation (P<0.0001), formed fewer tubules (P = 0.02), and migrated less (P = 0.049) than control. Vitamin D3 significantly improved preeclampsia ECFC functional properties. VDR- or VEGF blockade reduced tubule formation, partially restorable by vitamin D3.

Conclusion: Fetal ECFCs from preeclamptic pregnancies are reduced in number and dysfunctional. Vitamin D3 had rescuing effects. This may have implications for the increased cardiovascular risk associated with preeclampsia.

Show MeSH
Related in: MedlinePlus