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

J Am Heart Assoc. 2021 Sep 7;10(17):e020608. doi: 10.1161/JAHA.120.020608. Epub 2021 Aug 28.

Abstract

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.

Keywords: TRPV4; angiotensin II; astrocytes; calcium; neurovascular coupling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Angiotensin II Type 1 Receptor Blockers
  • Animals
  • Astrocytes / physiology*
  • Benzimidazoles
  • Biphenyl Compounds
  • Calcium
  • Calcium Signaling*
  • Cerebrovascular Circulation
  • Male
  • Mice, Inbred C57BL
  • Neurovascular Coupling*
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Vasoconstriction

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Biphenyl Compounds
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Angiotensin II
  • candesartan
  • Calcium

Grant support