Adenylyl cyclase 5–generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia
Arsalan U. Syed, … , Madeline Nieves-Cintrón, Manuel F. Navedo
Arsalan U. Syed, … , Madeline Nieves-Cintrón, Manuel F. Navedo
Published August 1, 2019; First published June 4, 2019
Citation Information: J Clin Invest. 2019;129(8):3140-3152. https://doi.org/10.1172/JCI124705.
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Research Article Cell biology Vascular biology

Adenylyl cyclase 5–generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia

Abstract

Elevated blood glucose (hyperglycemia) is a hallmark metabolic abnormality in diabetes. Hyperglycemia is associated with protein kinase A–dependent (PKA-dependent) stimulation of L-type Ca2+ channels in arterial myocytes resulting in increased vasoconstriction. However, the mechanisms by which glucose activates PKA remain unclear. Here, we showed that elevating extracellular glucose stimulates cAMP production in arterial myocytes, and that this was specifically dependent on adenylyl cyclase 5 (AC5) activity. Super-resolution imaging suggested nanometer proximity between subpopulations of AC5 and the L-type Ca2+ channel pore-forming subunit CaV1.2. In vitro, in silico, ex vivo, and in vivo experiments revealed that this close association is critical for stimulation of L-type Ca2+ channels in arterial myocytes and increased myogenic tone upon acute hyperglycemia. This pathway supported the increase in L-type Ca2+ channel activity and myogenic tone in 2 animal models of diabetes. Our collective findings demonstrate a unique role for AC5 in PKA-dependent modulation of L-type Ca2+ channel activity and vascular reactivity during acute hyperglycemia and diabetes.

Authors

Arsalan U. Syed, Gopireddy R. Reddy, Debapriya Ghosh, Maria Paz Prada, Matthew A. Nystoriak, Stefano Morotti, Eleonora Grandi, Padmini Sirish, Nipavan Chiamvimonvat, Johannes W. Hell, Luis F. Santana, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo

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Figure 2

AC activity is required for vascular L-type Ca2+ channel potentiation and vasoconstriction in response to increased glucose.

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AC activity is required for vascular L-type Ca2+ channel potentiation an...
(A and B) Exemplary nifedipine-sensitive IBa from WT arterial myocytes untreated (A) and pretreated with 2,5-DDA (B) in response to a voltage ramp before and after increasing of extracellular glucose from 10 mM to 20 mM. (C) Representative IBa traces showing changes in glucose-induced current during a ramp depolarization from –80 mV to +40 mV in 2,5-DDA–untreated (–) (black trace) and 2,5-DDA–treated (+) (green trace) cells. (D) Plot (mean ± SEM) of the integrated area under the curve (pA∙ms) of nifedipine-sensitive IBa recorded in response to a voltage ramp before and after increasing of extracellular glucose from 10 mM to 20 mM in –2,5-DDA and +2,5-DDA arterial myocytes (n = 8 cells from 5 mice for the –2,5-DDA group and n = 7 cells from 3 mice for the +2,5-DDA group). *P < 0.05, Wilcoxon matched-pairs signed-rank test. Significance was compared between 10 mM and 20 mM d-glucose for each data set. Cell capacitance was similar for the –2,5-DDA (14 ± 0.5 pF) and +2,5-DDA data sets (15.7 ± 1.5 pF; P = 0.5100, Mann-Whitney test). (E–G) Representative diameter recordings (E and F) and summary plot of changes in arterial tone (G) from pressurized (60 mmHg) WT arteries untreated (n = 6 arteries from 6 mice) and pretreated (n = 6 arteries from 4 mice) with 2,5-DDA in response to 20 mM d-glucose. *P < 0.05, Mann-Whitney test. Data represent mean ± SEM.