34 Decreased dilation of hippocampal arterioles in a rat model of preeclampsia

Abstract

Introduction Women with preeclampsia (PE) and eclampsia have increased incidence of white matter lesions in the brain and self-report cognitive impairment later in life, suggesting seizures during PE may lead to long-lasting brain injury. The hippocampus, a brain region central to cognition, is more susceptible to seizure-induced injury due to less effective functional hyperemia. How PE affects the function and structure of the hippocampal vasculature remains unknown, but could further limit functional hyperemia and potentiate seizure-induced injury. Objective We tested the hypothesis that hippocampal arterioles (HpAs) in PE have impaired responses to mediators of dilation generated during seizure including extracellular potassium (K+) and nitric oxide (NO) and undergo inward remodeling that limits blood flow to the hippocampus during seizure. Methods Sprague Dawley rats were nonpregnant (NP; n = 6), pregnant (P; d20; n = 6) or with PE (induced by a high cholesterol diet gestational days 7–20; n = 6). HpAs were isolated and pressurized to 60 mmHg in an arteriograph chamber. The function of HpAs was investigated by measuring changes in lumen diameter in response to the small- and intermediate-conductance calcium-activated potassium (SK/IK) channel agonist NS309, and in response to increasing K+ concentration from 3–15 mM to activate inward rectifier potassium (KIR) channels. Basal production of NO and the sensitivity of vascular smooth muscle to NO were investigated using the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10-3M) and the NO donor sodium nitroprusside (SNP; 10-5M), respectively. HpA structure and distensibility were determined by measuring lumen diameter and wall thickness of fully relaxed arterioles. Data are mean ± SEM and comparisons made using a one-way ANOVA with a post-hoc Bonferroni test. Results HpAs from PE rats dilated less when SK/IK channels were activated with NS309 compared to P and NP rats (55 ± 18% vs. 88 ± 2% and 90 ± 4%; p = 0.053). Activation of KIR with 15 mM K+ caused less dilation in HpAs from PE rats compared to P and NP rats, although this did not reach statistical significance (9 ± 8% vs. 61 ± 27% and 20 ± 11%; p = 0.13). NOS inhibition with L-NAME did not constrict any HpAs, suggesting there was no basal NO production. HpAs from PE rats were less sensitive to NO, with less reactivity to SNP compared to P and NP rats (22 ± 10% vs. 30 ± 10% and 38 ± 8%; p > 0.05). Structurally, lumen diameters were smaller in fully relaxed HpAs from PE rats than NP rats (Fig. 1), and vessel walls were thinner in PE and P rats compared to NP rats (7.7 ± 0.6 μm and 8.3 ± 0.7 μm vs. 11.5 ± 0.7 μm at 60 mmHg; p p Conclusion HpAs from PE rats had impaired dilatory responses, were less distensible, and underwent inward, hypotrophic remodeling making them structurally smaller than the NP and P states. This combination of impaired vasodilation and structural remodeling of HAs in PE could limit blood flow to the hippocampus during seizure, resulting in ischemic neuronal injury.