Vascular endothelial mitochondrial oxidative stress in response to preeclampsia: a role for angiotension II type 1 autoantibodies

Abstract

BACKGROUND: Preeclampsia is characterized by a new onset of hypertension during pregnancy and is associated with autoantibodies against the angiotensin II type 1 receptor and oxidative stress. There is growing evidence for mitochondrial dysfunction in preeclampsia, however, the culprits for mitochondrial dysfunction are still being defined. We previously demonstrated that angiotensin II type 1 autoantibodies cause renal, placental, and endothelial mitochondrial dysfunction in pregnant rats. However, the role of the angiotensin II type 1 autoantibodies in endothelial mitochondrial function in response to sera from preeclamptics is unknown. Thus, we hypothesized that circulating factors, such as the angiotensin II type 1 autoantibodies, during preeclampsia would negatively impact the vascular endothelial mitochondrial function in human umbilical vein endothelial cells. OBJECTIVE: The objective of the study was to determine a role for circulating angiotensin II type 1 autoantibodies to cause endothelial mitochondrial reactive oxygen species and dysfunction in preeclampsia compared to normal pregnant controls. STUDY DESIGN: Immediately after delivery, sera was collected from preeclamptic patients and normal pregnant controls. The mitochondrial reactive oxygen species were determined from the cells treated overnight with 10% sera from either the control or preeclamptic patients with and without the antiotension II type 1 autoantibodies inhibitor peptide ('n7AAc'). RESULTS: Preeclampsia patients at <34 weeks' gestation exhibited an elevated mean arterial blood pressure. Cells treated with serum from the preeclampsia patients at <34 weeks gestational age showed significantly (P<0.05) greater mitochondrial oxidative stress and reduced respiration than cells treated with the control sera, and these abnormalities were restored with 'n7AAc'. CONCLUSION: This study demonstrates that endothelial mitochondrial dysfunction occurs in response to circulating factors, especially in response to serum from preterm preeclampsia patients, and can be restored by blocking circulating angiotensin II type 1 autoantibodies, thereby indicating a potential new therapeutic target for preeclampsia.

Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia

“…Notably, we demonstrated that the blockade of circulating AT1-AA from human PE sera was able to attenuate mtROS in HUVECS cultured with PE sera with and without AT1-AA blockade [23]. In addition to the AT1-AA, our lab has recently investigated the importance of mt oxidative stress in PE pathology, and has linked reduced vascular endothelial mt respiration and mtROS with the presence of CD4+ T cells stimulated in response to placental ischemia [23][24][25][26][27][28][29]. In a previous study from our groups, we showed that LD recombinant IL-2 improved T regs cell in RUPP rats.…”

“…Previously, McCarthy [28] showed vascular mtROS and decreased respiration in HUVECs exposed to sera from PE patients compared to HUVECS cultured with sera from normal pregnant women, thus indicating the importance of the release of soluble factors in the circulation to cause cellular mt dysfunction. Notably, we demonstrated that the blockade of circulating AT1-AA from human PE sera was able to attenuate mtROS in HUVECS cultured with PE sera with and without AT1-AA blockade [23]. In addition to the AT1-AA, our lab has recently investigated the importance of mt oxidative stress in PE pathology, and has linked reduced vascular endothelial mt respiration and mtROS with the presence of CD4+ T cells stimulated in response to placental ischemia [23][24][25][26][27][28][29].…”

“…In addition, multiple factors can induce placental mitochondrial ROS production, and for example, we have previously shown that natural killer cells [4] and CD4+ T cells [29] cause mitochondrial dysfunction in RUPP rats and endothelial cells incubated with RUPP serum exhibit mitochondrial ROS [6]. HUVECS treated with serum from PE women and incubated with MitoSOX Red indicated that serum from PE women contained circulating factors which contribute to mitochondrial dysfunction and an increase in mt ROS in cultured human vascular endothelial cells, thereby demonstrating that an increase in oxidative stress contributes to endothelial dysfunction [6,23]. Furthermore, PE is associated with chronic immune activation, thereby leading to an increase in inflammatory cytokine production.…”

“…A compilation of research indicates that endothelial and mt dysfunction is readily observed in preeclamptic placentas [6,[18][19][20][21][22][23][24][25][26][27]. Previously, McCarthy [28] showed vascular mtROS and decreased respiration in HUVECs exposed to sera from PE patients compared to HUVECS cultured with sera from normal pregnant women, thus indicating the importance of the release of soluble factors in the circulation to cause cellular mt dysfunction.…”

Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

“…Notably, the elevated uterine vascular resistance is decreased by 'n7AAc', a capped inhibitory peptide binding to the AT 1 -AA and blocking AT 1 -AAs from binding to the AT 1 receptor [310]. Prolonged incubation of HUVECs with serum from preeclamptic patients suppresses mitochondrial respiration and increases mitochondrial ROS [311]. The increased mitochondrial ROS following exposure to serum from preeclamptic patients is reduced by 'n7AAC' [311].…”