Abstract
Preeclampsia is a hypertensive disorder of pregnancy. It is associated with abnormal placentation via poor placental invasion of the uterine vasculature by trophoblast cells, leading to poor placental perfusion, oxidative stress, and inflammation, all of which are implicated in its pathogenesis. A dyslipidemia characterized by low plasma levels of high-density lipoproteins (HDL) and elevated triglycerides has been described in preeclampsia. Apolipoprotein A-I (apoA-I), a constituent of HDL is an anti-inflammatory agent. This study investigated whether apoA-I protects against hypertension and adverse placental changes in a proinflammatory cytokine (TNF-α)-induced model of preeclampsia. Further, this study investigated whether apoA-I protects against the inhibitory effect of TNF-α in a human in vitro model of trophoblast invasion. Administration of apoA-I to pregnant mice before infusion with TNF-α resulted in a significant reduction in the cytokine-induced increase in systolic blood pressure. MRI measurement of T2 relaxation, a parameter that is tissue specific and sensitive to physiological changes within tissues, showed a reversal of TNF-α-induced placental changes. Preincubation of endothelial cells with apoA-I protected against the TNF-α-induced inhibition of HTR-8/SVneo (trophoblast) cell integration into endothelial (UtMVEC) networks. These data suggest that a healthy lipid profile may affect pregnancy outcomes by priming endothelial cells in preparation for trophoblast invasion.
Highlights
PREECLAMPSIA, the most significant and common complication of pregnancy, is characterized by hypertension and end-organ dysfunction, predominantly proteinuria
This study further examines whether apoA-I provides protection against the deleterious effects of TNF-␣ in a human in vitro model of trophoblast invasion and determines whether this protection is provided by modulation of adhesion molecules and markers of invasion that are implicated in trophoblast invasion of the uterine vasculature, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) [26], integrin ␣64, integrin ␣11, epithelial cadherin (E-cadherin), and vascular endothelial cadherin (VEcadherin) [29]
Experimental animals infused with TNF-␣ showed a significant increase in systolic blood pressure (BP) (16.2 mmHg Ϯ 1.71 mmHg) compared with saline-infused control animals (Ϫ5.71 mmHg Ϯ 1.49 mmHg) (P Ͻ 0.05) at gestational day 17 (Fig. 1)
Summary
PREECLAMPSIA, the most significant and common complication of pregnancy, is characterized by hypertension and end-organ dysfunction, predominantly proteinuria. A key factor in this condition’s pathogenesis has been shown to be poor placental invasion of the uterine vasculature by trophoblast cells [23], resulting in poor placental perfusion, placental oxidative stress, cellular damage and inflammation, and the release of antiangiogenic compounds into the maternal circulation [18]. This leads to endothelial dysfunction and the maternal hypertensive response. Studies using a human trophoblast-endothelium cell interaction model, demonstrated that TNF-␣ can interfere in vitro with trophoblast migration and integration into endothelial cellular networks [28] This is thought to mimic the early cell-to-cell placental interaction critical to normal placental development. It was reported that high-resolution maps based on T2 (spin-spin or transverse) relaxation times in MRI scans of live mouse placenta clearly differentiated between distinct regions of the placenta and that T2 values and ratios between regions were sensitive to the physiological changes within the tissue, such as loss of blood flow or TNF-␣ infusion [6]
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