Key factors

Preeclampsia studies

Vitamin D studies

Factors affecting placental trophoblastic invasion, implantation and vasculogenesis.

Key factors: Maternal: dNK cells, KIR2DL4

Fetal: HLA-G, HLA-C

1) dNK cells gene mutations with reduction in its proportion or phenotype variation.

2) Defects in genes expression of maternal KIR2DL4.

3) Strong inhibitory effect of maternal dNK cells KIR2DL4 ligand.

4) Defects fetal HLA-G and HLA-C RNA gene expression and protein.

1) Both decidua and trophoblastic cells express VDR.

2) Human decidua produces 1, 25 (OH) 2D (3) throughout pregnancy with highest expression in the first trimester.

3) In vitro human isolates of incomplete human EVT in first trimester express HLA-G. EVT responds to both Vitamin D (metabolite and its precursor) with significantly increased EVT invasion. Invasion was independent of cell viability.

Factors affecting placental Trophoblastic invasion, implantation and vasculogenesis.

Key factors: Altered innate and adaptive immune system

1) Imbalance between two subpopulations of CD4⁺ T cells. Unfavorable, uncontrolled hypoxic-related proinflammatory environment prevails impairing fetal tolerance and implantation:

a) Reversal of Th1/Th2; down regulated favorable Th2 type cytokines (IL-4, IL-10 and TGF-β) for pregnancy success; Upregulated, unfavorable Th1 cytokines (IL-2, IFN-Ɣ, TNF-α).

b) Reversal of the proinflammatory Treg/Th17 ratio. Tregs decrease and Th17 increase. Th17 produces IL17; both Th17 and neutrophils cause massive inflammation generating oxidative stress; and the presence of increase in both TNF-α and IL-6 contribute to endothelial damage/dysfunction.

2) Monocytes from preeclampsia patients express significantly increased levels of TLR4 and produce high concentrations of proinflammatory cytokines.

3) Abnormal systemic maternal humoral response.

1) Vitamin D restores the balance between Th1 and Th2 type cytokines. By favoring Th2 domination, it modifies the uncontrolled proinflammatory environment resulting from the hypoxic state.

2) Vitamin D increases the expression of IL-10 and decreases the expression of Th1 mediated proinflammatory cytokines (IFN-Ɣ, IL-2, and TNF-α); this function limits oxidative stress during ischemia and prevents rejection of the fetal allograft.

3) TNF-α-expressed in Th1 cells is significantly higher during Vitamin D deficiency. Calcitriol has a dose-dependent inhibition of the expression of TNF-α and IL-6, down-regulating their proinflammatory nature during hypoxia.

4) Calcitriol induces TGF-β which interacts with NK cells, to allow acceptance of trophoblasts and avoid fetal cells death.

5) In the absence of Vitamin D, monocytes numbers and its TLR4 are decreased, reducing its ability to be proinflammatory.

6) Vitamin D is a potent regulator of CAMP an essential antibacterial hormone that supports successful implantation.

Role of HO-1

1) HO-1-deficiency is characteristic of preeclampsia. Any genetic polymorphism of HO-1 affects placental development and is associated with reduced stress defense (no response to proinflammatory cytokines with increased susceptibility to vascular damage).

2) Hypoxia/oxidative stress cause increased TXA (a potent vasoconstrictor and facilitator of platelet aggregation) and decreased PGI (a potent vasodilator).

1) Pretreatment of 1, 25 (OH) 2D (3) to hypoxia/oxidative stress model resulted in a significantly reduced TXA and reduced ratio of TXA to PGI, to promote circulation and retard thrombosis in the placenta.

2) The direct role Vitamin Don HO-1 pathways remain to be clarified.

Factors affecting placental angiogenesis:

Key factors: Angiogenic Vs. Antiangiogenic factors

1) High circulating antiangiogenic factors: -(sFlt-1 and sEng) as predictive biomarkers of preeclampsia. -African American with preeclampsia have angiogenic imbalance involving significantly lower levels of PlGF, higher sFlt-1 and a higher sFlt-1/PLGF ratio.

2) Low circulating angiogenic factors: -VEGF and PlGF.

1) Vitamin D regulation of angiogenic factors remains unclear.

2) Maternal PlGF levels significantly lower with 25 (OH) D < 50 nmol/L; and both low levels of maternal 25 (OH) D and PlGF levels were inversely associated with the risk of preeclampsia.

3) Combining both 25 (OH) D level and sFlt-1/PLGF ratio was more predictive than either alone for the development of severe preeclampsia.

4) The Vitamin D supplementation to PE-induced rat model group showed restoration of angiogenic balance and reduction of inflammation in PE-induced hypertension.