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.
Losartan, an angiotensin II (AT1) receptor antagonist, preserves cerebral blood flow in hypertensive patients with a history of stroke
