AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat

Abstract

Banek CT, Bauer AJ, Needham KM, Dreyer HC, Gilbert JS. AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat. Am J Physiol Heart Circ Physiol 304: H1159 -H1165, 2013. First published February 15, 2013 doi:10.1152/ajpheart.00903.2012.-Previous studies suggest restoration of angiogenic balance can lower blood pressure and improve vascular endothelium function in models of preeclampsia. Our laboratory has recently reported exercise training mitigates hypertension in an animal model of preeclampsia, but the mechanisms are unknown. AMP-activated protein kinase (AMPK) is stimulated during exercise and has been shown to increase expression of VEGF. Therefore, the purpose of this study was to determine whether AICAR (5-aminoimidazole-4-carboxamide-3-ribonucleoside), a potent AMPK stimulator, would increase circulating VEGF, improve angiogenic potential, decrease oxidative stress, and abrogate placental ischemia-induced hypertension. In rats, reduced uteroplacental perfusion pressure (RUPP) was induced on day 14 of gestation by introducing silver clips on the inferior abdominal aorta and ovarian arteries. AICAR was administered intraperitoneally (50 mg/kg b.i.d.) days 14 -18, and blood pressure and tissues were collected on day 19. RUPP-induced hypertension was ameliorated (P Ͻ 0.05) with AICAR versus RUPP. AICAR increased (P Ͻ 0.05) plasma VEGF and decreased (P Ͻ 0.05) plasma soluble VEGF receptor-1 in the RUPP ϩ AICAR versus RUPP. Antioxidant capacity was restored (P Ͻ 0.05) by AICAR in RUPP placenta. Renal and placental catalase activity was decreased (P Ͻ 0.05) in RUPP ϩ AICAR versus RUPP. Angiogenic potential was increased (P Ͻ 0.05) in RUPP ϩ AICAR versus RUPP. Fetal and placental weights were unaffected by AICAR. Placental AMPK phosphorylation was increased (P Ͻ 0.05) in RUPP ϩ AICAR versus normal pregnant and RUPP. These findings suggest AICAR may be useful to mitigate angiogenic imbalance, renal, and placental oxidative stress and increase in blood pressure associated with RUPP hypertension. Furthermore, placental AMPK phosphorylation was observed only in the setting of ischemia. preeclampsia; hypertension; angiogenic balance; 5-aminoimidazole-4-carboxamide-3-ribonucleoside PREECLAMPSIA, A pregnancy-specific syndrome, is the leading cause of fetal and maternal morbidity and mortality across the world, and unfortunately the incidence has been increasing in recent decades (32, 35). Currently, there are limited treatments available, and early delivery is often indicated to prevent further progression of the syndrome. Consequently, preeclampsia is the leading cause of premature delivery, which is well known to have numerous deleterious effects on neonatal and life-long health (32,35).Recent clinical and experimental studies suggest dysregulation of circulating angiogenic factors results in an angiogenic imbalance that is most notably characterized by an altered ratio of pro-angiogenic (e.g., VEGF) and anti-angiogenic factors (e.g., soluble VEGF receptor-1, or s...

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

“…Although various in vitro and in vivo models have been used to study the etiology of PE [38][39][40], such as exposure of trophoblast cells to hypoxia and hypoxia/reoxygenation [41][42][43][44], induction of 'PE-like' trophoblast cell metabolic alterations had not previously been demonstrated. Our data show that persistent exposure to 1% oxygen for 24 h was required to activate AMPK in HTR8/SVneo cells, indicating that trophoblast cells were resistant to low oxygenation.…”

“…Although Banek and colleagues have shown that pharmacological activation of AMPK in the Reduced Uterine Perfusion Pressure (RUPP)-induced PE rat model ameliorates hypertension [38], the protective effects of AMPK activation on PE are probably largely derived from its regulatory function on angiogenesis rather than on trophoblast invasion. Therefore, the timing and type of AMPK modulation should be carefully tailored to the intended effect.…”

Methodological differences account for inconsistencies in reported free VEGF concentrations in pregnant rats

“…These ELISAs will be referred to as either the rat VEGF ELISA or mouse VEGF ELISA for the remainder of the paper. Previous investigators have interpreted these ELISAs as measuring free (5,7,14) or total (20) VEGF; however, R&D Systems does not specify what the kits measure. Therefore, we have simply referred to these measurements as VEGF in the results and discussion.…”

Systemic Therapies for Malignant Pheochromocytoma and Paraganglioma Can Exacerbate Hypertension

“…Furthermore, Lankhorst and coworkers 3 indicated that activation of the ET-1 axis may support the use of ET receptor antagonists for the treatment of angiogenesis inhibition-induced hypertension, especially because ET receptor stimulation in vascular smooth muscle cells results in VEGF production and mitogenesis in a mitogen-activated protein kinase pathway-dependent manner. What's more, Banek and colleagues 4 showed that AMP-activated protein kinase (AMPK) is stimulated during exercise and has been shown to increase expression of VEGF. Therefore, using a potent AMPK stimulator would increase circulating VEGF, improve angiogenic potential, decrease oxidative stress, and abrogate placental ischemiainduced hypertension.…”

“…Lastly, some hypothesize that TKIs can cause tumor cell apoptosis, leading to release of stored catecholamines and metanephrines and worsening hypertension. 4 Interestingly, in vitro studies in PC-12 rat pheochromocytoma cells suggest that sunitinib inhibits tyrosine hydroxylase activity thereby ultimately decreasing catecholamine production. 6 Based on the literature and our experience, we suggest that patients with malignant PCC/PGL receiving any systemic therapy should be evaluated for pretreatment with a-blockers or calcium channel blockers, similar to the perioperative blockade, to prevent exacerbation of hypertension.…”