Correlation between Apelin and Some Angiogenic Factors in the Pathogenesis of Preeclampsia: Apelin-13 as Novel Drug for Treating Preeclampsia and Its Physiological Effects on Placenta

Abstract

Preeclampsia (PE) is one of the commonest causes for maternal and fetal morbidity and mortality. Imbalances of angiogenic factors, oxidative stress, and inflammatory response have a role in the pathogenesis of PE. Data regarding the circulating apelin level and its role in PE remains controversial. This study was formulated to assess the serum apelin level in PE, investigate its correlation with some inflammatory, oxidative stress, and angiogenic proteins in a nitric oxide synthase inhibitor; the N (gamma)-nitro-L-arginine methyl ester (L-NAME)-induced rat model of PE and determine whether apelin administration could protect against development of PE. 40 healthy adult female albino rats and 10 adult male albino rats were used in this study. The pregnant female rats were randomly divided into three groups: group 1 (normal pregnant group), group 2 (PE-induced group), injected subcutaneously with 75 mg L-NAME/kg bodyweight/day starting from day 9 to 20 of gestation, and group 3 (PE-induced group supplemented with apelin (PE + apelin)); PE induced as before and simultaneously subcutaneously injected with apelin-13 (6 × 10−8 mol/kg bodyweight/twice daily) beginning from day 6 to 20 of gestation. In all groups, blood pressure and urine protein were determined at gestation days (GD) 0, 10, and 18. Moreover, serum apelin, placental growth factor (PLGF), vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), interferon-gamma (IFN-γ), and interleukin-10 (IL-10) levels and serum superoxide dismutase enzyme (SOD) and catalase (CAT) activities of all groups were estimated at the end of experiment. Placental histopathological examination was also performed. PE-induced rats showed significantly decreased serum apelin levels. Moreover, they showed significantly increased blood pressures, urine proteins, sFlt-1, sEng, and IFN-γ (mean arterial blood pressure, urine proteins, sFlt-1, sEng, and IFN-γ showed significant negative correlations with serum apelin level), but it showed significantly decreased VEGF, PLGF, IL-10, SOD, and CAT (VEGF, PLGF, IL-10, and SOD showed significant positive correlations with serum apelin level). In contrast, exogenous apelin administration significantly ameliorated these parameters together with improvement in the placental histoarchitecture in the apelin-supplemented PE group. This study demonstrated the protective effects of apelin administration on the pathogenesis of PE.

The Apelinergic System in Pregnancy

“…Regarding apelin, Hamza et al found that PE-induced rats (L-NAME) showed significantly decreased apelin serum levels [97]. Moreover, they observed significantly increased blood pressure and urine proteins.…”

“…Moreover, they observed significantly increased blood pressure and urine proteins. These parameters negatively correlated with the serum apelin level, and exogenous apelin-13 administration significantly improved them, together with an improvement in the placental histoarchitecture [97]. Accordingly, in reduced uterine perfusion pressure PE-induced rats, Wang et al observed that apelin-13 treatment significantly improved the symptoms of PE, suggesting that apelin may be a potential target for treating PE [39].…”

“…Effect of administration of apelin and ELA peptides during pregnancy pathologies [39,97,140,157,158].…”

The Yin and Yang Effect of the Apelinergic System in Oxidative Stress

“…Hence, maternal concentrations of apelin lower than expected may play a key role in the etiology of PE. Circulating apelin concentrations showed a significant negative correlation with mean arterial blood pressure, proteinuria, serum soluble fms-like tyrosine kinase-1 (sFlt-1, a soluble form of VEGF/PLGF receptors which acts as an effective scavenger of VEGF and PLGF and sensitizes maternal endothelium to proinflammatory cytokines, thus inducing endothelial dysfunction and multiorgan damage), soluble endoglin (sEng, that acts as a limiting factor for eNOS activity), and IFN-γ levels in PE compared to control women [72]. Furthermore, a positive correlation of apelin levels with serum placental growth factor (PLGF), VEGF and IL-10 levels, and superoxide dismutase (SOD) and catalase activities was also recognized [72].…”

Apelin, APJ, and ELABELA: Role in Placental Function, Pregnancy, and Foetal Development—An Overview

“…In conclusion, the different results between apelin/APJ/ELABELA expression in various compartments of the placenta and maternal plasma level in PE [ 85 , 135 , 136 , 137 , 138 , 139 , 140 , 141 ] may be explained by several factors such as: apelin corelation with different hormones/growth factors (e.g., VEGF, PLGF, IL-10 [ 154 ]), degree of intensity of PE (mild/severe cases) [ 155 ], or other environmental factors such as maternal age, smoking, or even BMI [ 138 ]. Based on the literature data, apelin inhibited the development of the rat model of PE; administration of apelin twice a day to rats significantly reduced the unfavorable symptoms of PE, which in turn was beneficial in repairing impaired endothelial nitric oxide synthase/NO signaling, and reduced the activation of oxidative stress in the rat model [ 144 ].…”