Placental Ischemia Impairs Middle Cerebral Artery Myogenic Responses in the Pregnant Rat

Abstract

One potential mechanism contributing to the increased risk for encephalopathies in women with preeclampsia is altered cerebral vascular autoregulation resulting from impaired myogenic tone. Whether placental ischemia, a commonly proposed initiator of preeclampsia, alters cerebral vascular function is unknown. This study tested the hypothesis that placental ischemia in pregnant rats (induced by reducing uterine perfusion pressure, RUPP) leads to impaired myogenic responses in middle cerebral arteries (MCA). Mean arterial pressure (in mmHg) was increased by RUPP (135±3) compared with normal pregnant rats (NP, 103±2) and non-pregnant controls (Ctrl, 116±1). MCA from rats sacrificed on gestation day 19 were assessed in a pressure ateriograph under active (+ Ca2+) and passive (0 Ca2+) conditions while luminal pressure was varied between 25 and 150 mmHg. The slope of the relationship between tone and pressure in the MCA was 0.08±0.01 in CTRL rats and was similar in NP rats (0.05±0.01). In the RUPP model of placental ischemia, this relationship was markedly reduced (slope = 0.01±0.00, p<0.05). Endothelial dependent and independent dilation was not different between groups nor was there evidence of vascular remodeling assessed by the wall:lumen ratio and calculated wall stress. The impaired myogenic response associated with brain edema measured by % water content (RUPP p<0.05 vs. CTRL and NP). This study demonstrates that placental ischemia in pregnant rats leads to impaired myogenic tone in the MCA and that the RUPP model is a potentially important tool to examine mechanisms leading to encephalopathy during preeclamptic pregnancies.

Magnesium Sulfate Prevents Placental Ischemia-Induced Increases in Brain Water Content and Cerebrospinal Fluid Cytokines in Pregnant Rats

“…Placental ischemia-induced increase in brain water content was prevented by MgSO 4 treatment. The increase in brain water content in response to placental ischemia is consistent with studies showing edema in preeclampsia patients (Mitas and Rogulski, 2012), and the placental ischemic model (Ryan et al, 2011; Warrington et al, 2014). It should be noted that a recent paper reported decreased brain water content in the posterior cerebrum of rats subjected to placental ischemia plus a high cholesterol diet (Johnson et al, 2014).…”

“…Additionally, placental ischemia leads to increased circulating and placental levels of inflammatory cytokines (LaMarca et al, 2005; Gadonski et al, 2006), and increased anti-angiogenic factors (Gilbert et al, 2007, 2009), along with similar cerebrovascular changes as preeclampsia patients. Recent studies have shown marked impairment in cerebral blood flow autoregulation, increased BBB permeability, (Warrington et al, 2014) impaired cerebrovascular myogenic tone, and cerebral edema (Ryan et al, 2011) in response to placental ischemia. Importantly, a recent study by Johnson et al demonstrated increases in BBB permeability and microglial activation following placental ischemia and high cholesterol to mimic severe preeclampsia (Johnson et al, 2014).…”

Placental ischemia increases seizure susceptibility and cerebrospinal fluid cytokines

“…) along with impaired cerebrovascular myogenic tone and edema (Ryan et al. ). While placental ischemia shares numerous characteristics of preeclampsia in patients, whether placental ischemia increases seizure susceptibility and whether it can be utilized as a potential animal model of eclampsia is not known.…”

Recent Advances in the Understanding of the Pathophysiology of Preeclampsia

“…Acute increases in blood pressure activate the vascular myogenic response, protecting neuronal tissue from damage. Women with severe preeclampsia have increased cerebral blood flow and perfusion pressure 78 and our lab recently demonstrated impaired myogenic tone in the middle cerebral arteries and cerebral edema in placental ischemic rats 79 . These conditions of increased cerebral blood flow and impaired myogenic reactivity render preeclamptic patients susceptible to neurological complications with acute increases in blood pressure.…”