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.
View: Text | PDF
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

×

Figure 4

AC5 is necessary for increased myogenic tone of cerebral arteries in response to elevated glucose in vivo.

Options: View larger image (or click on image) Download as PowerPoint
AC5 is necessary for increased myogenic tone of cerebral arteries in res...
(A) Overview of the open cranial window. Black arrowheads indicate exemplary arteries that were used for analysis. (B–K) Representative images of middle cerebral arteries and branches (white arrows) visualized through an open cranial window and used to analyze diameter changes in response to 10 mM d-glucose (B and G) and in response to 20 mM d-glucose (C and H), 10 mM d-glucose + 10 mM mannitol (D and I), and 0 Ca2+ + 1 μM nifedipine (E and J) in WT and AC5–/– mice (n = 8 arteries from 2 mice per group). The yellow arrows point to veins. (F and K) Summary percent myogenic tone in response to 10 mM d-glucose, 10 mM d-glucose + 10 mM mannitol, and 20 mM d-glucose. *P < 0.05, ANOVA with Tukey’s multiple-comparisons test for each group. Data represent mean ± SEM.