Our goal is to understand the mechanisms by which cerebrovascular insult induced by neonatal seizures causes sustained loss of cerebral blood flow regulation. Circulating endothelial cells (CECs) in the peripheral blood are indicative of vascular damage in cardiovascular disease, but relationships between CECs and cerebrovascular insults have not been investigated. Cerebral blood flow regulation is compromised following seizures in newborn pigs. This proposal is based on our exciting preliminary data suggesting seizures cause appearance of brain-derived circulating endothelial cells (BCECs) in blood coincident with cerebrovascular endothelial injury and a loss endothelial cerebrovascular dilatory function. Further, in newborn pig cerebral vascular endothelial cells, the seizure-inducing excitatory neurotransmitter, glutamate, causes oxidative stress, apoptosis, and cell detachment. We hypothesize that seizure-evoked BCECs are systemic biomarkers of cerebral vascular damage that originate from oxidative stress-induced endothelial apoptosis and endothelial sloughing from cerebral vessels that contributes to sustained loss of endothelial-dependent vasodilator functions in the neonatal cerebral circulation. To test this hypothesis, four specific aims will be addressed using in vivo and in vitro approaches in newborn pigs: 1) Characterize, in vivo, time-dependent relationships among seizures, cerebrovascular events, oxidative stress, and BCECs. 2) Test, in vivo, the hypothesis that BCECs originate via seizure-induced endothelial apoptosis leading to sloughing of cerebral vascular endothelial cells;3) Test, in cerebral vascular endothelial cells, the hypothesis that glutamate receptor activation produces Ca2+ overload that causes oxidative stress-induced apoptosis and leads to cell detachment;4) Investigate, in vivo, the causal relationships among BCECs, oxidative stress, and the severity of seizure-related loss of endothelial-dependent vasodilator functions in the neonatal cerebral circulation. These experiments are novel both by combining in vivo and in vitro approaches to study the mechanisms of seizure-induced loss of cerebral blood flow regulation and by investigating, for the first time, brain-derived circulating endothelial cells as well as their association with neonatal cerebral vascular injury. Seizures in the neonatal period cause life-long neurological disabilities. Cerebral vascular dysfunction may contribute to seizure-induced neurological sequilae. Understanding mechanisms of seizure-related loss of cerebral blood flow regulation and finding correlations between cerebrovascular insult and systemic parameters is essential in improving the long-term neurological outcome of human newborns.
Seizures are the most frequent neurological event in the neonatal period that can cause morbidity and mortality in newborns and life-long neurological disabilities in survivors, and cerebral vascular dysfunction may contribute to neurological sequilae. Brain- derived circulating endothelial cells in peripheral blood are of potential importance as non-invasive markers of cerebrovascular insults. Understanding mechanisms of seizure-related loss of cerebral blood flow regulation and finding correlations between cerebrovascular insult and systemic parameters is essential in improving the long-term neurological outcome of human newborns.
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