G protein-mediated signaling in the myogenic response – role of Rho-kinase and aging

TY - ABST

T1 - G protein-mediated signaling in the myogenic response – role of Rho-kinase and aging

AU - Björling, Karl

AU - Joseph, Philomeena Daphne

AU - Egebjerg, Kristian

AU - Hansen, Jakob Lerche

AU - Salomonsson, Max

AU - Jensen, Lars Jørn

PY - 2017

Y1 - 2017

N2 - A myogenic response (MR) is a reflex vasoconstriction to an increase in intraluminal pressure, which is crucial for autoregulation of tissue blood flow and basal, myogenic tone (MT) in resistance vessels. Development of MT is suggested to involve mechanical activation of G protein-coupled receptors. Aim: 1) to investigate the signaling events from Gq/11 and/or G12 activation to MT development; 2) to elucidate the impact of aging. We used pressure myography, calcium imaging, Q-PCR and immunofluorescence to study small (lumen D < 200 µm) mesenteric arteries (SMA) from young (2-3 months), mature adult (6-7 months), and old (12-13 months) wildtype (C57BL6) mice. Theoretical blood flow calculations in SMA indicated autoregulation of blood flow at pressures from 60 to 120 mm Hg. Gq/11 and G12 were abundantly expressed at the mRNA and protein levels in SMA, and the Gα/q inhibitor YM-254890 (0.1 µM) suppressed MT development. The Phosholipase C inhibitors U73122 (0.5 µM) and ET18-OCH3 (10 µM) robustly inhibited MT, and the TRPC channel blocker SKF 96365 (10 µM) slightly reduced MT. There was a significant effect of age (P<0.0001) with MT being increased in mature adult mice and reduced in old mice compared to young mice. The ROCK2 inhibitor KD025 (5 µM) robustly inhibited MT in all mice, but this effect was significantly larger in mature adult mice. Our data suggest that MT development in SMAs is initiated by phosphorylation of Myosin Light Chain through a Gq/11/PLC/TRPC-dependent pathway, and is sustained via a ROCK2-mediated Ca2+ sensitization. Increased MT at mature adulthood may be explained by increased ROCK2 activity.

AB - A myogenic response (MR) is a reflex vasoconstriction to an increase in intraluminal pressure, which is crucial for autoregulation of tissue blood flow and basal, myogenic tone (MT) in resistance vessels. Development of MT is suggested to involve mechanical activation of G protein-coupled receptors. Aim: 1) to investigate the signaling events from Gq/11 and/or G12 activation to MT development; 2) to elucidate the impact of aging. We used pressure myography, calcium imaging, Q-PCR and immunofluorescence to study small (lumen D < 200 µm) mesenteric arteries (SMA) from young (2-3 months), mature adult (6-7 months), and old (12-13 months) wildtype (C57BL6) mice. Theoretical blood flow calculations in SMA indicated autoregulation of blood flow at pressures from 60 to 120 mm Hg. Gq/11 and G12 were abundantly expressed at the mRNA and protein levels in SMA, and the Gα/q inhibitor YM-254890 (0.1 µM) suppressed MT development. The Phosholipase C inhibitors U73122 (0.5 µM) and ET18-OCH3 (10 µM) robustly inhibited MT, and the TRPC channel blocker SKF 96365 (10 µM) slightly reduced MT. There was a significant effect of age (P<0.0001) with MT being increased in mature adult mice and reduced in old mice compared to young mice. The ROCK2 inhibitor KD025 (5 µM) robustly inhibited MT in all mice, but this effect was significantly larger in mature adult mice. Our data suggest that MT development in SMAs is initiated by phosphorylation of Myosin Light Chain through a Gq/11/PLC/TRPC-dependent pathway, and is sustained via a ROCK2-mediated Ca2+ sensitization. Increased MT at mature adulthood may be explained by increased ROCK2 activity.

U2 - 10.1159/000480116

DO - 10.1159/000480116

M3 - Conference abstract in journal

C2 - 28858872

SN - 1018-1172

VL - 54

SP - 9

JO - Journal of Vascular Research

JF - Journal of Vascular Research

IS - S2

M1 - 8

T2 - 12th International Symposium on Resistance Arteries

Y2 - 3 September 2017 through 6 September 2017

ER -