scholarly journals Angiotensin II Disrupts Neurovascular Coupling by Potentiating Calcium Increases in Astrocytic Endfeet

2021 ◽  
Author(s):  
Michaël Boily ◽  
Lin Li ◽  
Diane Vallerand ◽  
Hélène Girouard
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Dicarboxylic Acid ◽  
Neurovascular Coupling ◽  
At1 Receptor ◽  
Ang Ii ◽  
Vascular Response ◽  
Intracellular Ca ◽  
Astrocytic Endfeet

Background Angiotensin II (Ang II), a critical mediator of hypertension, impairs neurovascular coupling. Since astrocytes are key regulators of neurovascular coupling, we sought to investigate whether Ang II impairs neurovascular coupling through modulation of astrocytic Ca 2+ signaling. Methods and Results Using laser Doppler flowmetry, we found that Ang II attenuates cerebral blood flow elevations induced by whisker stimulation or the metabotropic glutamate receptors agonist, 1S, 3R‐1‐aminocyclopentane‐ trans ‐1,3‐dicarboxylic acid ( P <0.01). In acute brain slices, Ang II shifted the vascular response induced by 1S, 3R‐1‐aminocyclopentane‐ trans ‐1,3‐dicarboxylic acid towards vasoconstriction ( P <0.05). The resting and 1S, 3R‐1‐aminocyclopentane‐ trans ‐1,3‐dicarboxylic acid–induced Ca 2+ levels in the astrocytic endfeet were more elevated in the presence of Ang II ( P <0.01). Both effects were reversed by the AT1 receptor antagonist, candesartan ( P <0.01 for diameter and P <0.05 for calcium levels). Using photolysis of caged Ca 2+ in astrocytic endfeet or pre‐incubation of 1,2‐Bis(2‐aminophenoxy)ethane‐ N,N,N',N' ‐tetra‐acetic acid tetrakis (acetoxymethyl ester), we demonstrated the link between potentiated Ca 2+ elevation and impaired vascular response in the presence of Ang II ( P <0.001 and P <0.05, respectively). Both intracellular Ca 2+ mobilization and Ca 2+ influx through transient receptor potential vanilloid 4 mediated Ang II‐induced astrocytic Ca 2+ elevation, since blockade of these pathways significantly prevented the intracellular Ca 2+ in response to 1S, 3R‐1‐aminocyclopentane‐ trans ‐1,3‐dicarboxylic acid ( P <0.05). Conclusions These results suggest that Ang II through its AT1 receptor potentiates the astrocytic Ca 2+ responses to a level that promotes vasoconstriction over vasodilation, thus altering cerebral blood flow increases in response to neuronal activity.

Selective Blockade of AT1 Receptor Attenuates Impairment of Hypotensive Autoregulation and Improves Cerebral Blood Flow after Brain Injury in the Newborn Pig

2003 ◽  
Vol 99 (5) ◽  
pp. 1118-1124 ◽  
Author(s):  
Dimitry Baranov ◽  
William M. Armstead
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Receptor Activation ◽  
At1 Receptor ◽  
Sham Control ◽  
Fluid Percussion ◽  
Fluid Percussion Injury ◽  
At1 Antagonist ◽  
Severe Hypotension

Background Fluid percussion injury (FPI) in piglets produces vasoconstriction of pial arteries (PAs), decreases in cerebral blood flow (CBF), and impairment of hypotensive autoregulation. Two types of angiotensin II receptors, AT1 and AT2, have been identified in the brain. This study characterized the effect of pretreatment with AT1- and AT2-selective antagonists on CBF and hypotensive autoregulation after FPI. Methods Fluid percussion injury was induced in chloralose-anesthetized newborn pigs equipped with closed cranial windows. CBF was determined by the radiolabeled microsphere technique. Results Moderate and severe hypotension (71 +/- 3, 53 +/- 2, and 40 +/- 1 mmHg for normotension, moderate hypotension, and severe hypotension, respectively) elicited PA dilation without changes in CBF in sham control piglets. The AT1 antagonist ZD 7155 partially restored impaired hypotension-induced PA dilation after FPI (19 +/- 1 and 34 +/- 1 vs. 5 +/- 1 and 7 +/- 1 vs. 12 +/- 1 and 20 +/- 3% for PA dilation during moderate and severe hypotension in sham control, FPI, and FPI + ZD 7155 animals, respectively). ZD 7155 also blunted the reductions in CBF during normotension and hypotension observed in untreated animals (43 +/- 4, 38 +/- 5, and 55 +/- 3 vs. 32 +/- 4, 19 +/- 2, and 27 +/- 5% CBF reductions during normotension, moderate hypotension, and severe hypotension in untreated and pretreated animals, respectively). The AT2 selective antagonist PD 123,319 did not restore hypotension-induced PA dilation and did not prevent decreases in CBF observed during normotension and moderate and severe hypotension after FPI. Conclusion These data indicate that blockade of the AT1 and not the AT2 receptor diminished the reduction in hypotensive PA dilation after FPI. AT1 blockade also blunted the decrease in CBF during normotension as well as the further decrease in CBF observed during hypotension after FPI. These data suggest that AT1 receptor activation by angiotensin II contributes to cerebrovascular dysregulation during hypotension after FPI.

FC 016SPARSENTAN IMPROVES GLOMERULAR BLOOD FLOW AND AUGMENTS PROTECTIVE TISSUE REMODELING IN MOUSE MODELS OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Georgina Gyarmati ◽  
Urvi Shroff ◽  
Audrey Izuhara ◽  
Radko Komers ◽  
Patricia Bedard ◽  
...  
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Tissue Remodeling ◽  
At1 Receptor ◽  
Capillary Blood ◽  
Capillary Blood Flow ◽  
Ang Ii ◽  
Receptor Antagonism ◽  
Filtration Barrier ◽  
Genetically Engineered Mice

Abstract Background and Aims Preliminary preclinical and emerging clinical evidence indicates strong antiproteinuric actions of dual endothelin type A (ETA) and angiotensin II type 1 (AT1) receptor antagonism with sparsentan. These nephroprotective effects have been more pronounced in different experimental and clinical settings compared to current standard of care using an AT1 receptor blocker (ARB). Considering the broad spectrum of renal actions of endothelin (ET) and angiotensin II (Ang II), inhibition of both pathways using sparsentan is postulated to target multiple renal cell types via a variety of renoprotective mechanisms. The aim of this study was to determine glomerular action of sparsentan as compared to the ARB losartan (Los) by direct visualization of effects on renal hemodynamics and tissue remodeling in the intact living kidney. Method Intravital multiphoton microscopy (MPM) of the glomerular vasculature and filtration barrier structure and function was performed in genetically engineered mice combined with traditional urinalysis and histology-based phenotyping. Glomerular hemodynamic parameters (afferent and efferent arteriole (AA and EA) diameters and single nephron glomerular filtration rate (SNGFR)) and podocyte calcium entry, as a measure of cell injury, were quantitatively visualized in the FSGS model Pod-GCaMP5/Tomato TRPC6 transgenic mice (1.5 years of age), in which TRPC6 is overexpressed together with the calcium reporter GCaMP5 in podocytes. Single cell identification and fate tracking of cells of the renin lineage (CoRL) was performed over time using a second physiologic control mouse model, Ren1d-Confetti mice that feature a multicolor CFP/GFP/YFP/FP reporter. Three groups of mice in each model received treatment with either vehicle (CTRL), the ARB losartan (Los; 10 mg/kg/day), or sparsentan (120 mg/kg/day) for 6 weeks (FSGS model) or 2 weeks (control physiology model). Results Both Los and sparsentan treatment attenuated the acute ET + Ang II-induced elevation of podocyte calcium by ∼80%, and the development of albuminuria, and glomerulosclerosis and tissue fibrosis in the FSGS model. Notably, sparsentan prevented the ET + Ang II increases in podocyte calcium more than Los and was significantly more effective in dilating both AA and EA (Fig. 1A, B), increasing SNGFR (Fig. 1C), increasing capillary blood flow (2-fold; p&lt;0.0001 vs. CTRL), and decreasing albuminuria (20%; p&lt;0.05 vs. CTRL). Sparsentan also preserved p57+ podocyte number by 50% compared to Los (p&lt;0.0001 vs. Los). Similarly, pretreatment with sparsentan was more effective in preventing glomerular arteriolar vasoconstriction induced by acute ET + Ang II iv injection compared to Los (p&lt;0.05 vs. Los). Following a 2-week treatment in control healthy Ren1d-Confetti mice, sparsentan resulted in a more robust increase compared to Los in the number of Confetti+ cells, clones, and individual cells per clone in the glomeruli and AA (Fig. 1D-F). Renal tubule segments also showed active cellular remodeling in response to sparsentan. Conclusion Serial MPM imaging directly visualized several mechanisms underlying beneficial antiproteinuric and structural effects of sparsentan in both FSGS and in the normal mouse kidney and differences between dual ETA/AT1 receptor antagonism of sparsentan and a mono-selective ARB. The sparsentan-induced glomerular hemodynamic pattern was driven by both AA and EA dilation resulting in an increase in capillary blood flow. Compared to Los, sparsentan was more effective in attenuating ET/Ang II-induced podocyte injury and in activation of resident progenitor cells and tissue remodeling. These findings suggest multiple layers of renal protective actions by dual ETA and AT1 receptor antagonism.

scholarly journals IL-17A Contributes to the Angiotensin II-induced Neurovascular Coupling impairment through Oxidative Stress

2021 ◽  
Author(s):  
Jessica Youwakim ◽  
Diane Vallerand ◽  
Helene Girouard
Keyword(s):  
Oxidative Stress ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Neurovascular Coupling ◽  
Flow Regulation ◽  
Ang Ii ◽  
Superoxide Anion Production ◽  
Blood Flow Regulation ◽  
Chronic Inflammatory Condition ◽  
The Relationship

Abstract Hypertension, a multifactorial chronic inflammatory condition, is a risk factor for neurodegenerative diseases including stroke and Alzheimer’s disease. These diseases have been associated with higher concentration of blood interleukin (IL)-17A. However, the role that IL-17A plays in the relationship between hypertension and brain remains misunderstood. Cerebral blood flow regulation may be the crossroads of these conditions. Hypertension alters cerebral blood flow regulation including neurovascular coupling (NVC). In the present study, the effects of IL-17A on NVC in the context of hypertension induced by angiotensin (Ang) II will be examined. Our results show that the neutralization of IL-17A or the specific inhibition of its receptor prevent the Ang II- induced NVC impairment. These treatments reduce the Ang II-induced cerebral oxidative stress. Tempol and NOX-2 depletion prevent NVC impairment induced by IL-17A. These findings suggest that IL-17A, through superoxide anion production, is an important mediator of cerebrovascular dysregulation induced by Ang II.

Pulmonary vascular response to angiotensin II in canine pacing-induced heart failure

1996 ◽  
Vol 271 (1) ◽  
pp. H222-H227 ◽  
Author(s):  
B. J. Roy ◽  
V. H. Pitts ◽  
M. I. Townsley
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Venous Pressure ◽  
Left Ventricular ◽  
Microvascular Permeability ◽  
Ang Ii ◽  
Vascular Response

The effects of angiotensin II(ANG II) on pulmonary vascular resistance and microvascular permeability were studied in isolated, blood-perfused, ventilated canine lung lobes from control animals (n = 40) and animals with pacing-induced heart failure (n = 15). Conditioned dogs were paced (245 beats/min) for 30.6 +/- 0.9 (SE) days until left ventricular shortening fraction decreased by 56% (P < 0.05). Baseline pulmonary arterial resistance (Ra) (19.1 +/- 1.6 vs. 8.0 +/- 1.1 cmH2O.1(-1).min.100g) and venous resistance (Rv) (17.1 +/- 2.3 vs. 7.8 +/- 1.0 cmH2O.1(-1).min.100 g) were greater (P < 0.05) in the paced group compared with controls, respectively. Increments in Ra (delta Ra) and Rv(delta Rv) were measured after intra-arterial boluses of ANG II (1-10 micrograms). ANG II produced a dose-dependent response in delta Ra that was enhanced after pacing (P < 0.05). There was no effect on delta Rv in either group. At increased venous pressure (Pv = 20 cmH2O), the increments in delta Ra were significantly attenuated in both groups. In control lobes at low Pv, delta Ra and delta Rv both tended to decrease with increased lobar blood flow, suggesting that blood flow affects the pulmonary vascular response of ANG II. The baseline capillary filtration coefficient (Kf,c) was not different in the paced group compared with control, nor was there any effect of ANG II on Kf,c in the paced group. However, Kf,c did increase after ANG II in the control groups evaluated at either low or high Pv (P < 0.05). This difference in Kf,c was not seen if the experiment was done at increased Pv but without ANG II administration. We conclude that the pulmonary vasoconstrictor activity of ANG II is modestly enhanced in canine pacing-induced heart failure. Nonetheless, ANG II does not likely contribute to increased pulmonary vascular resistance in vivo in heart failure, since this effect was abolished at increased Pv. Finally, the absence of any effect of ANG II on pulmonary microvascular permeability in the paced group is suggestive of some adaptive remodeling of the capillary endothelial barrier.

scholarly journals The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Junie P. Warrington ◽  
Fan Fan ◽  
Jeremy Duncan ◽  
Mark W. Cunningham ◽  
Babette B. LaMarca ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
At1 Receptor ◽  
Type I ◽  
Pregnant Rats ◽  
Doppler Flowmetry ◽  
Cerebrovascular Function ◽  
Placental Ischemia

Abstract Background Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure. Methods Placental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry. Results Placental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content. Conclusions These results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia.

scholarly journals The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension

2011 ◽  
Vol 300 (1) ◽  
pp. H397-H407 ◽  
Author(s):  
Carmen Capone ◽  
Giuseppe Faraco ◽  
Laibaik Park ◽  
Xian Cao ◽  
Robin L. Davisson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Time Course ◽  
Ang Ii ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Blood Flow Increase

Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by “slow pressor” angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice ( n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng·kg−1·min−1), AP started to rise after 9 days ( P < 0.05 vs. saline), remained elevated at 11–17 days, and returned to baseline at 21 days ( P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng·kg−1·min−1) induced cerebrovascular dysfunction and oxidative stress without elevating AP ( P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng·kg−1·min−1) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.

scholarly journals Neurovascular Coupling and Epilepsy: Hemodynamic Markers for Localizing and Predicting Seizure Onset

2007 ◽  
Vol 7 (4) ◽  
pp. 91-94 ◽  
Author(s):  
Theodore H. Schwartz
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Neurovascular Coupling ◽  
Epileptic Activity ◽  
Tissue Hypoxia ◽  
Epileptic Focus ◽  
Seizure Onset

Hemodynamic surrogates of epileptic activity are being used to map epileptic foci with PET, SPECT, and fMRI. However, there are few studies of neurovascular coupling in epilepsy. Recent data indicate that cerebral blood flow, although focally increased at the onset of a seizure, may be temporarily inadequate to meet the metabolic demands of both interictal and ictal epileptic events. Transient focal tissue hypoxia and hyperperfusion may be excellent markers for the epileptic focus and may even precede the onset of the ictal event.

Angiotensin II induces insulin resistance independent of changes in interstitial insulin

1999 ◽  
Vol 277 (5) ◽  
pp. E920-E926 ◽  
Author(s):  
Joyce M. Richey ◽  
Marilyn Ader ◽  
Donna Moore ◽  
Richard N. Bergman
Keyword(s):  
Insulin Resistance ◽  
Heart Rate ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Glucose Uptake ◽  
Peripheral Resistance ◽  
Glucose Turnover ◽  
Ang Ii

We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 ± 16 to 94 ± 14 mmHg, P < 0.001) with a compensatory decrease in heart rate (110 ± 7 vs. 86 ± 4 mmHg, P < 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg ⋅ ml−1⋅ min ( P < 0.05). ANG II infusion increased femoral artery blood flow (176 ± 4 to 187 ± 5 ml/min, P < 0.05) and resulted in additional increases in both plasma and lymph insulin (93 ± 20 to 122 ± 13 μU/ml and 30 ± 4 to 45 ± 8 μU/ml, P < 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 ± 1.2 vs. 5.4 ± 0.7 mg ⋅ kg−1⋅ min−1, P > 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin.

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