scholarly journals APOE4 genotype increases neuronal calcium signals and decreases pial arteriole responsivity and vasomotion in visual cortex of awake mice

2021 ◽  
Author(s):  
Orla Bonnar ◽  
Kira Shaw ◽  
Dori M Grijseels ◽  
Devin Clarke ◽  
Laura Bell ◽  
...  
Keyword(s):  
Blood Flow ◽  
Visual Stimulation ◽  
Late Onset ◽  
Vascular Dysfunction ◽  
Beta Amyloid ◽  
Blood Oxygenation ◽  
Vascular Density ◽  
Calcium Signals ◽  
Doppler Flowmetry ◽  
Acute Surgery

Vascular dysfunction is an early feature of late onset Alzheimer's disease (AD), preceding classic AD pathology such as beta amyloid accumulation and formation of hyperphosphorylated tau. Such vascular dysfunction may promote classic AD pathology by decreasing blood flow, impairing brain oxygenation and clearance of molecules such as beta amyloid. The main genetic risk factor for AD is the ϵ4 allele of APOE, which has been found to increase blood brain barrier permeability and decrease vascular density, as well as decrease blood flow and functional hyperaemia in anaesthetised mice undergoing acute surgery. These results suggest that APOE4 may confer AD risk via its effects on the vasculature. However, the responses of neurons and individual vessels have not been studied, so neurovascular relationships are unknown, and no previous studies have looked at awake mice. We therefore measured neurovascular responses at rest and in response to visual stimulation using 2 photon imaging of awake APOE3 and APOE4 targeted-replacement (APOE TR) mice that expressed the calcium indicator GCaMP6f in excitatory neurons, while labelling the vascular lumen with Texas Red dextran. In parallel, we measured cerebral blood flow, blood oxygenation and cerebral blood volume using combined laser Doppler flowmetry and haemoglobin spectrometry. Measurements were performed in mice aged between 3-4 months to 12-13 months. We found a milder vascular deficit in awake mice than previous studies that used an acute surgical preparation: capillary responses to visual stimulation were the same in APOE3 and APOE4 TR mice, leading to unimpaired functional hyperaemia. However, neuronal calcium signals during visual stimulation were significantly enhanced in APOE4 mice, while there was a marked decrease in pial arteriole responsiveness and vasomotion. This pattern of results was unaffected by age, suggesting that APOE4 expression creates a stable, but mildly altered neurovascular state that does not itself cause degeneration. However, these changes likely make the system more sensitive to subsequent insults; for example, weaker vasomotion could impair clearance of beta amyloid as it starts to accumulate, and therefore may help explain how APOE4 expression increases risk of developing AD.

scholarly journals Kidney dysfunction in the low-birth weight murine adult: implications of oxidative stress

2018 ◽  
Vol 315 (3) ◽  
pp. F583-F594 ◽  
Author(s):  
Wasan Abdulmahdi ◽  
May M. Rabadi ◽  
Edson Jules ◽  
Yara Marghani ◽  
Noor Marji ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Birth Weight ◽  
Endothelial Dysfunction ◽  
Low Birth Weight ◽  
Vascular Dysfunction ◽  
Vascular Density ◽  
Immunofluorescence Analysis ◽  
Doppler Flowmetry ◽  
Maternal Undernutrition ◽  
Nephron Endowment

Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.

scholarly journals Oxygen Tension and Blood Flow in Relation to Revascularization in Transplanted Adult and Fetal Rat Pancreatic Islets

2002 ◽  
Vol 11 (8) ◽  
pp. 813-820 ◽  
Author(s):  
Per-Ola Carlsson ◽  
Göran Mattsson
Keyword(s):  
Blood Flow ◽  
Pancreatic Islets ◽  
Oxygen Tension ◽  
Blood Perfusion ◽  
Vascular Density ◽  
Low Oxygen ◽  
Doppler Flowmetry ◽  
Rat Pancreatic Islets ◽  
Low Oxygen Tension ◽  
Fetal Islets

We have previously recorded a decreased oxygen tension and blood flow in syngeneically transplanted rat pancreatic islets. The present study related measurements of oxygen tension and blood flow to the vascular density in such grafts implanted beneath the renal capsule. We also evaluated whether transplanted fetal islets are better revascularized than adult islets, and if the degree of revascularization is directly related to the islet vascular endothelial growth factor (VEGF) production. Tissue pO2 was measured using Clark microelectrodes, whereas islet graft blood flow was measured with laser-Doppler flowmetry. The vascular density of endogenous and transplanted islets was quantified in histological specimens stained with the lectin Bandeiraea simplicifolia (BS-1). Tissue pO2 in the transplanted adult and fetal islet grafts was similar and markedly lower than in the endogenous islets. The blood perfusion of both the adult and fetal islet grafts was 60–65% of that in the renal cortex. Administration of d-glucose did not affect tissue pO2 in either the endogenous or transplanted islets, nor graft blood perfusion. The number of capillaries found in the transplanted adult and fetal islets was similar and markedly lower than in endogenous islets. However, in the connective tissue stroma, which constituted ~20% of all islet grafts, the vascular density was higher than in the corresponding endocrine parts of these grafts. Incubated adult islets released higher amounts of VEGF than fetal islets. In conclusion, the previously described low oxygen tension of syngeneically transplanted adult rat islets is related to a low vascular density. Similar low oxygen tension and vascular density are seen in grafted fetal islets. The amount of VEGF production does not correlate to the degree of revascularization of the grafts.

scholarly journals mTOR drives cerebral blood flow and memory deficits in LDLR−/− mice modeling atherosclerosis and vascular cognitive impairment

2017 ◽  
Vol 38 (1) ◽  
pp. 58-74 ◽  
Author(s):  
Jordan B Jahrling ◽  
Ai-Ling Lin ◽  
Nicholas DeRosa ◽  
Stacy A Hussong ◽  
Candice E Van Skike ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cognitive Impairment ◽  
Cognitive Dysfunction ◽  
Cardiovascular Health ◽  
Vascular Dysfunction ◽  
Brain Inflammation ◽  
Vascular Density ◽  
Mtor Inhibition ◽  
Markers Of Inflammation

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer’s disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR−/− mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

Abstract 266: Renovascular Remodeling in Hypertensive Dahl-SS Rats: Role of MMP Inhibitor as a Hypertension Ameliorating Agent

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Sourav Kundu ◽  
Sathnur Pushpakumar ◽  
Naira Metriveli ◽  
Suresh C Tyagi ◽  
Utpal Sen
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Vascular Density ◽  
High Salt Diet ◽  
Doppler Flowmetry ◽  
Cortical Blood Flow ◽  
Mmp Inhibitor ◽  
Arterial Blood ◽  
Renal Cortical Blood Flow ◽  
Renal Vascular

High salt diet has long been associated with chronic hypertension. The development of renal injury in Dahl salt-sensitive (SS) hypertensive rats is characterized by structural and functional changes involving vascular remodeling. Increased activity of matrix metalloproteinases (MMPs) leading to alteration in the extracellular matrix (ECM) is the main mechanism contributing to increased peripheral vascular resistance. In this study, we hypothesized that inhibition of MMPs will modulate ECM remodeling by decreasing MMP activity and thus reduce mean arterial blood pressure. METHODS: We used Dahl-salt sensitive (Dahl-SS) and Lewis rats fed on high salt diet. The groups were 1) Dahl-SS, 2) Dahl-SS+GM6001 (non-specific MMP inhibitor), 3) Lewis, and 4) Lewis+GM6001. GM6001 was given at 0.5mg/mL by intra-peritoneal injection on alternate days for 3 weeks. Blood pressure, laser doppler flowmetry for renal cortical blood flow and barium angiography for renal vascular density were measured. Results: Mean arterial blood pressure was 172.10 ± 0.57 mm Hg in hypertensive Dahl-SS rats compared to 136.12 ± 1.22 mm Hg in Dahl-SS+GM6001 rats. The mean arterial pressures in lewis and lewis+GM6001 groups were 97.08 ± 0.56 and 87.63 ± 2.93 mm Hg respectively. Laser doppler flowmetry showed reduced renal cortical blood flow (1333.33 flux units) in Dahl-SS rats compared to Dahl-SS rats treated with GM6001 (1605 flux units). Lewis rats showed similar renal cortical flow with (1488.33 flux units) or without GM6001 (1425 flux units). Barium angiography demonstrated increased renal vascular density with patent branches in the renal cortex of animals treated with MMP inhibitor, GM6001. Conclusion: Our results suggest that in hypertensive Dahl-SS rats, inhibition of MMP attenuates high blood pressure, maintains patency of renal cortical vessels thus improving cortical blood flow.

scholarly journals Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation

2009 ◽  
Vol 30 (4) ◽  
pp. 1120-1132 ◽  
Author(s):  
Beau M. Ances ◽  
Christine L. Liang ◽  
Oleg Leontiev ◽  
Joanna E. Perthen ◽  
Adam S. Fleisher ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Visual Stimulation ◽  
Oxygen Metabolism ◽  
Blood Oxygenation Level Dependent ◽  
Blood Oxygenation ◽  
Blood Oxygenation Level ◽  
Oxygenation Level ◽  
Effects Of Aging

scholarly journals Effect of hypoxia on BOLD fMRI response and total cerebral blood flow in migraine with aura patients

2017 ◽  
Vol 39 (4) ◽  
pp. 680-689 ◽  
Author(s):  
Nanna Arngrim ◽  
Anders Hougaard ◽  
Henrik W Schytz ◽  
Mark B Vestergaard ◽  
Josefine Britze ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Healthy Volunteers ◽  
Migraine With Aura ◽  
Neuronal Excitability ◽  
Visual Stimulation ◽  
Blood Oxygenation ◽  
Bold Response ◽  
Double Blind ◽  
Signal Response

Experimentally induced hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura (MA). We investigated the blood oxygenation level-dependent (BOLD) signal response to visual stimulation during hypoxia in MA patients and healthy volunteers. In a randomized double-blind crossover study design, 15 MA patients were allocated to 180 min of normobaric poikilocapnic hypoxia (capillary oxygen saturation 70–75%) or sham (normoxia) on two separate days and 14 healthy volunteers were exposed to hypoxia. The BOLD functional MRI (fMRI) signal response to visual stimulation was measured in the visual cortex ROIs V1–V5. Total cerebral blood flow (CBF) was calculated by measuring the blood velocity in the internal carotid arteries and the basilar artery using phase-contrast mapping (PCM) MRI. Hypoxia induced a greater decrease in BOLD response to visual stimulation in V1–V4 in MA patients compared to controls. There was no group difference in hypoxia-induced total CBF increase. In conclusion, the study demonstrated a greater hypoxia-induced decrease in BOLD response to visual stimulation in MA patients. We suggest this may represent a hypoxia-induced change in neuronal excitability or abnormal vascular response to visual stimulation, which may explain the increased sensibility to hypoxia in these patients leading to migraine attacks.

scholarly journals Hemodynamic Changes after Visual Stimulation and Breath Holding Provide Evidence for an Uncoupling of Cerebral Blood Flow and Volume from Oxygen Metabolism

2008 ◽  
Vol 29 (1) ◽  
pp. 176-185 ◽  
Author(s):  
Manus J Donahue ◽  
Robert D Stevens ◽  
Michiel de Boorder ◽  
James J Pekar ◽  
Jeroen Hendrikse ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cerebral Blood Volume ◽  
Visual Stimulation ◽  
Functional Neuroimaging ◽  
Oxygen Metabolism ◽  
Blood Oxygenation ◽  
Breath Holding ◽  
Breath Hold ◽  
Bold Signal

Functional neuroimaging is most commonly performed using the blood-oxygenation-level-dependent (BOLD) approach, which is sensitive to changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and the cerebral metabolic rate of oxygen (CMRO2). However, the precise mechanism by which neuronal activity elicits a hemodynamic response remains controversial. Here, visual stimulation (14 secs flashing checkerboard) and breath-hold (4 secs exhale + 14 secs breath hold) experiments were performed in alternating sequence on healthy volunteers using BOLD, CBV-weighted, and CBF-weighted fMRI. After visual stimulation, the BOLD signal persisted for 33 ± 5 secs (n = 9) and was biphasic with a negative component (undershoot), whereas CBV and CBF returned to baseline without an undershoot at 20 ± 5 and 20 ± 3 secs, respectively. After breath hold, the BOLD signal returned to baseline (23 ±7 secs) at the same time ( P < 0.05) as CBV (21 ± 6 secs) and CBF (18 ±3 secs), without a poststimulus undershoot. These data suggest that the BOLD undershoot after visual activation reflects a persistent increase in CMRO2. These observations support the view that CBV and CBF responses elicited by neuronal activation are not necessarily coupled to local tissue metabolism.

scholarly journals Model of Blood–Brain Transfer of Oxygen Explains Nonlinear Flow-Metabolism Coupling During Stimulation of Visual Cortex

2000 ◽  
Vol 20 (4) ◽  
pp. 747-754 ◽  
Author(s):  
Manouchehr S. Vafaee ◽  
Albert Gjedde
Keyword(s):  
Blood Flow ◽  
Oxygen Consumption ◽  
Visual Cortex ◽  
Metabolic Rate ◽  
Oxygen Diffusion ◽  
Visual Stimulation ◽  
Blood Oxygenation ◽  
Nonlinear Flow ◽  
Diffusion Capacity ◽  
Positron Emission

The coupling between cerebral metabolic rate of oxygen (CMRO2) and blood flow (CBF) in response to visual stimulation was evaluated by means of a model of oxygen delivery. The model predicted a nonlinear relationship between stimulus-evoked changes of oxygen consumption and blood flow. The magnitude of the CMRO2/CBF ratio index ( IO2) was used to indicate the degree of flow-metabolism coupling prevailing in specific areas of the brain during physiological stimulation. Therefore, the index provided a measure of the blood oxygenation level dependent (BOLD) magnetic resonance contrast. To evaluate the changes of IO2 in response to visual stimulation, the model was applied to the effect of a changing flicker rate of a visual stimulus on the magnitudes of CBF, CMRO2, and oxygen diffusion capacity, in the human brain. Positron emission tomography (PET) was used to measure the CBF and the CMRO2 in 12 healthy volunteers who viewed a cross-hair (baseline) or a yellow-blue annular checkerboard reversing at frequencies of 1, 4, or 8 Hz. The magnitude of CBF in the primary visual cortex increased as a function of the checkerboard reversal rate and reached a maximum at the frequency of 8 Hz ( z = 16.0), while the magnitude of CMRO2 reached a maximum at 4 Hz ( z = 4.0). Therefore, the calculated IO2 was lower at 8 Hz than at 1 and 4 Hz, in contrast to the oxidative metabolic rate that reached its maximum at 4 Hz. The model explained the increase of oxygen consumption as the combined effect of increased blood flow and increased oxygen diffusion capacity in the region of visual activation.

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