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

Journal of the American Heart Association (2021-08-31)
Michaël Boily, Lin Li, Diane Vallerand, Hélène Girouard

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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ elevation and impaired vascular response in the presence of Ang II (P<0.001 and P<0.05, respectively). Both intracellular Ca2+ mobilization and Ca2+ influx through transient receptor potential vanilloid 4 mediated Ang II-induced astrocytic Ca2+ elevation, since blockade of these pathways significantly prevented the intracellular Ca2+ 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 Ca2+ responses to a level that promotes vasoconstriction over vasodilation, thus altering cerebral blood flow increases in response to neuronal activity.

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Ionomycin, Free Acid, Streptomyces conglobatus - CAS 56092-81-0 - Calbiochem, Ionomycin, Free Acid, Streptomyces conglobatus, CAS 56092-81-0, is a highly specific for divalent cations and more effective than A23187 (Cat. No. 100105) as a mobile ion carrier for Ca2+.