Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy

Abstract

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p < 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p < 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE.

Serum Progesterone is Negatively Associated with Hypertension and Blood Pressure Indicators Among Men and Postmenopausal Women

“…Progesterone protects vasodilation by regulating levels of cytokines (such as interleukin-6), which can block inflammation. In two clinical trial studies, negative associations of progesterone with DBP and MAP were found, which is consistent with our results [26][27][28]. In accordance with our findings, the results of the above studies have also shown that progesterone is not associated with SBP in men [29,30].…”

Maternal immune suppression during pregnancy does not prevent abnormal behavior in offspring

“…In an arginine vasopressin model of PreE, male offspring of PreE dams exhibited increased social behavior in the three-chamber social preference task relative to control offspring, without there being a significant difference in distance travelled between the groups [ 53 ]. Our study is not without limitations, firstly even though it has previously been demonstrated that these animal models have hypertension and inflammation during pregnancy we did not directly evaluate that in the dams that birthed the offspring used in the current study [ 20 , 54 ]. We also did not measure the immune profile of these offspring as immune activation during pregnancy can be correlated with neurodevelopmental outcome of offspring [ 55 ].…”

Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model

“…Teran et al showed that women with PE have already-established alterations in the levels of mitochondria targeting antioxidant coenzyme (CoQ10) in the plasma and in the placenta, as compared to normal pregnant women ( Teran et al, 2001 ; Smith et al, 2021 ). Improved mitochondrial function and ROS are associated with improved blood pressure in sFLT-1-induced hypertensive pregnant rats ( Deer et al, 2021 ). CALCA is shown to protect myocardial cells against oxidative stress through a mitochondrial-dependent pathway, suggesting the involvement of mitochondria in the vascular action of CALCA ( Tullio et al, 2017 ).…”