Maternal hypertension during pregnancy modifies the response of the immature brain to hypoxia–ischemia: Sequential MRI and behavioral investigations

Letourneur, Annelise; Freret, Thomas; Roussel, Simon; Boulouard, Michel; Divoux, Didier; Toutain, Jérôme; Bernaudin, Myriam; Schumann-Bard, Pascale; Bouët, Valentine; Touzani, Omar

doi:10.1016/j.expneurol.2011.10.014

Cited by 14 publications

(7 citation statements)

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“…Despite these caveats, however, the results from this previous study ( 30 ) appear consistent with ours. That a 40 min MCAo duration may result in pure SNL outcome in Wistar rats as compared to 15 min in SHR is consistent with the well-established greater sensitivity to ischemia in the latter ( 31 ) due to poorer pial collaterals ( 32 ). Accordingly, in our previous set of studies using 45 min md-tMCAo in SHRs, the majority of subjects exhibited infarction ( 18 , 26 ).…”

Section: Discussionsupporting

confidence: 75%

What is the Optimal Duration of Middle-Cerebral Artery Occlusion Consistently Resulting in Isolated Cortical Selective Neuronal Loss in the Spontaneously Hypertensive Rat?

et al. 2015

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Introduction and objectives: Selective neuronal loss (SNL) in the reperfused penumbra may impact clinical recovery and is thus important to investigate. Brief proximal middle cerebral artery occlusion (MCAo) results in predominantly striatal SNL, yet cortical damage is more relevant given its behavioral implications and that thrombolytic therapy mainly rescues the cortex. Distal temporary MCAo (tMCAo) does target the cortex, but the optimal occlusion duration that results in isolated SNL has not been determined. In the present study, we assessed different distal tMCAo durations looking for consistently pure SNL.Methods: Microclip distal tMCAo (md-tMCAo) was performed in ~6-month old male spontaneously hypertensive rats (SHRs). We previously reported that 45 min md-tMCAo in SHRs results in pan-necrosis in the majority of subjects. Accordingly, three shorter MCAo durations were investigated here in decremental succession, namely 30, 22, and 15 min (n = 3, 3, and 7 subjects, respectively). Recanalization was confirmed by MR angiography just prior to brain collection at 28 days and T2-weighted MRI was obtained for characterization of ischemic lesions. NeuN, OX42, and GFAP immunohistochemistry appraised changes in neurons, microglia, and astrocytes, respectively. Ischemic lesions were categorized into three main types: (1) pan-necrosis; (2) partial infarction; and (3) SNL.Results: Pan-necrosis or partial infarction was present in all 30 min and 22 min subjects, but not in the 15 min group (p < 0.001), in which isolated cortical SNL was consistently present. MRI revealed characteristic hyperintense abnormalities in all rats with pan-necrosis or partial infarction, but no change in any 15 min subject.Conclusion: We found that 15 min distal MCAo consistently resulted in pure cortical SNL, whereas durations equal or longer than 22 min consistently resulted in infarcts. This model may be of use to study the pathophysiology of cortical SNL and its prevention by appropriate interventions.

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Section: Discussionsupporting

confidence: 75%

What is the Optimal Duration of Middle-Cerebral Artery Occlusion Consistently Resulting in Isolated Cortical Selective Neuronal Loss in the Spontaneously Hypertensive Rat?

et al. 2015

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“…One might also argue that such very low P t O 2 values indicate that the affected tissue is already irreversibly damaged (i.e., the ‘core’), and hence that NBO might not have enhanced P t O 2 in such conditions, resulting in unchanged FMISO lesion volumes. However, even though SHRs have worse hypoperfusion [ 33 – 35 ] and hypoxia after MCAo than Wistar rats (as shown here), they do have an extensive penumbra initially [ 33 – 35 , 62 ], and early interventions such as reperfusion and hyperoxia but also drugs do salvage the penumbra and reduce final infarct in SHRs [ 31 , 47 , 63 – 66 ], indicating that NBO should have affected FMISO uptake and retention, albeit probably less so than in Wistar rats.…”

Section: Discussionmentioning

confidence: 99%

“…To test this hypothesis, we assessed not only brain tracer retention at the standard 2-3hrs post-administration time, but also FMISO kinetic rate constants, specifically the irreversible trapping constant thought to reflect tissue hypoxia, by dynamically acquiring FMISO brain data since administration time and applying our previously reported quantitative kinetic model [ 32 ]. In addition, to assess the effects of hyperoxia on FMISO uptake in distinct tissue situations, we used both Wistar rats and their spontaneously hypertensive counterparts (SHRs), whose tissue vulnerability to focal cerebral ischemia, namely rate of demise of the severely hypoxic but viable tissue (i.e., the penumbra) [ 33 – 35 ] and final infarct volume [ 33 , 36 – 40 ], widely differ as a result of underlying differences in functionality and structure of the pial vascular tree [ 39 , 41 – 45 ], in turn mimicking clinical heterogeneity. In parallel to testing the effects of hyperoxia on FMISO uptake, and to inform the findings thereof, we also assessed its effects on tissue oxygen tension in both ischemic and non-ischemic cortex in a different group of animals.…”

Section: Introductionmentioning

confidence: 99%

Effects of hyperoxia on 18F-fluoro-misonidazole brain uptake and tissue oxygen tension following middle cerebral artery occlusion in rodents: Pilot studies

et al. 2017

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PurposeMapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET) is the gold standard hypoxia imaging method. Normobaric hyperoxia (NBO) is a promising therapy in acute stroke. In this pilot study, we tested the straightforward hypothesis that NBO would markedly reduce FMISO uptake in ischemic brain in Wistar and spontaneously hypertensive rats (SHRs), two rat strains with distinct vulnerability to brain ischemia, mimicking clinical heterogeneity.MethodsThirteen adult male rats were randomized to distal middle cerebral artery occlusion under either 30% O2 or 100% O2. FMISO was administered intravenously and PET data acquired dynamically for 3hrs, after which magnetic resonance imaging (MRI) and tetrazolium chloride (TTC) staining were carried out to map the ischemic lesion. Both FMISO tissue uptake at 2-3hrs and FMISO kinetic rate constants, determined based on previously published kinetic modelling, were obtained for the hypoxic area. In a separate group (n = 9), tissue oxygen partial pressure (PtO2) was measured in the ischemic tissue during both control and NBO conditions.ResultsAs expected, the FMISO PET, MRI and TTC lesion volumes were much larger in SHRs than Wistar rats in both the control and NBO conditions. NBO did not appear to substantially reduce FMISO lesion size, nor affect the FMISO kinetic rate constants in either strain. Likewise, MRI and TTC lesion volumes were unaffected. The parallel study showed the expected increases in ischemic cortex PtO2 under NBO, although these were small in some SHRs with very low baseline PtO2.ConclusionsDespite small samples, the apparent lack of marked effects of NBO on FMISO uptake suggests that in permanent ischemia the cellular mechanisms underlying FMISO trapping in hypoxic cells may be disjointed from PtO2. Better understanding of FMISO trapping processes will be important for future applications of FMISO imaging.

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“…In animal studies, at postnatal day 7, rat pups from spontaneously hypertensive mothers, exposed to hypoxic-ischemic brain injury, exhibited less brain damage than pups from normotensive mothers (Letourneur et al, 2012). Interestingly, this apparently protective phenomenon was associated with deficits in motor coordination and spatial learning in pups from hypertensive, compared to normotensive mothers.…”

Section: Endothelial Dysfunction and Impaired Angiogenesis In Offsprimentioning

confidence: 99%

Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming

et al. 2014

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Preeclampsia is a pregnancy-specific syndrome, defined by such clinical hallmarks as the onset of maternal hypertension and proteinuria after 20 weeks of gestation. The syndrome is also characterized by impaired blood flow through the utero-placental circulation and relative placental ischemia, which in turn, may generate feto-placental endothelial dysfunction. Endothelial dysfunction in offspring born from preeclamptic pregnancies has been associated with an increased risk of cardiovascular disease, including hypertension, later in life. Interestingly, diminished endothelial function, manifested by low angiogenic capacity, leads to hypertension in animal studies. Recently, we have shown that the adenosine receptor A2A/nitric oxide/vascular endothelial growth factor axis is reduced in human umbilical vein endothelial cells derived from preeclamptic pregnancies, an effect correlated with gestational age at onset of preeclampsia. We and others suggested that impaired vascular function might be associated with high cardiovascular risk in offspring exposed to pregnancy diseases. However, we are not aware of any studies that examine impaired adenosine-mediated angiogenesis as a possible link to hypertension in offspring born from preeclamptic pregnancies. In this review, we present evidence supporting the hypothesis that reduced adenosine-mediated angiogenesis during preeclamptic pregnancies might be associated with development of hypertension in the offspring.

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Maternal hypertension during pregnancy modifies the response of the immature brain to hypoxia–ischemia: Sequential MRI and behavioral investigations

Cited by 14 publications

References 50 publications

What is the Optimal Duration of Middle-Cerebral Artery Occlusion Consistently Resulting in Isolated Cortical Selective Neuronal Loss in the Spontaneously Hypertensive Rat?

What is the Optimal Duration of Middle-Cerebral Artery Occlusion Consistently Resulting in Isolated Cortical Selective Neuronal Loss in the Spontaneously Hypertensive Rat?

Effects of hyperoxia on 18F-fluoro-misonidazole brain uptake and tissue oxygen tension following middle cerebral artery occlusion in rodents: Pilot studies

Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming

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