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 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 7

AC5 expression mediates increased myogenic tone in HFD and STZ arteries in ex vivo and in vivo preparations.

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AC5 expression mediates increased myogenic tone in HFD and STZ arteries ...
Exemplary diameter recordings over a pressure range (from 10 to 100 mmHg) and plot summarizing percent myogenic tone obtained using arteries from WT mice (A; LFD: n = 6 arteries from 6 mice; HFD: n = 6 arteries from 5 mice) and AC5–/– mice (B; LFD: n = 5 arteries from 5 mice; HFD: n = 6 arteries from 6 mice) on LFD and HFD (*P < 0.05, Mann-Whitney test). Dashed lines represent passive diameter. (C) Representative images of middle cerebral arteries and branches (white arrows) visualized through an open cranial window from sham- and STZ-treated WT mice (n = 36 arteries from 5 mice for sham and n = 77 arteries from 6 mice for STZ) and AC5–/– mice (n = 38 arteries from 4 mice for sham and n = 73 arteries from 7 mice for STZ). The right panel shows a plot of percent myogenic tone from sham- and STZ-treated WT and AC5–/– mice. *P < 0.05, Mann-Whitney test between data sets from the same genotype. Data represent mean ± SEM.