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Updated: Mar 30, 2026
Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues
Published on: June 3, 2019
Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein
Angela Wirth1, Shengpeng Wang2, Mikito Takefuji2
1Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany Institute of Pharmacology, University of Heidelberg, ImNeuenheimer Feld 366, 69120 Heidelberg, Germany angela.wirth@pharma.uni-heidelberg stefan.offermanns@mpi-bn.mpg.de.
Insights
Age-dependent hypertension in mice is linked to activated vascular smooth muscle signaling, not vessel stiffness. Targeting these pathways offers a reversible treatment for elevated blood pressure.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Hypertension Pathogenesis
Background:
- Arterial hypertension is a significant risk factor for cardiovascular diseases.
- Mechanisms of hypertension, particularly age-dependent increases in blood pressure, remain incompletely understood.
- The role of vascular smooth muscle and G-protein signaling in hypertension requires further elucidation.
Purpose of the Study:
- To investigate the role of procontractile G-protein-mediated signaling pathways in vascular smooth muscle in the context of age-dependent hypertension.
- To understand the molecular mechanisms contributing to elevated blood pressure with aging.
Main Methods:
- Utilized 1-year-old mice exhibiting elevated blood pressure, mirroring human mid-life hypertension.
- Assessed vascular function, including vessel stiffness, endothelial dysfunction, reactive oxygen species (ROS) production, and endothelin-1 (ET-1) expression.
- Employed genetic manipulation using tamoxifen-inducible smooth muscle-specific conditional mouse knock-out models to inactivate specific G-protein signaling components (Gα12/Gα13, Gαq/Gα11, LARG) and ETA receptors.
Main Results:
- Aged hypertensive mice displayed endothelial dysfunction, increased vascular ROS, and elevated endothelial ET-1, but not increased vessel stiffness or impaired renal function.
- Age-dependent hypertension was normalized by ETA receptor blockade and smooth muscle-specific inactivation of the ETA receptor gene.
- Disruption of downstream signaling pathways (Gα12/Gα13, Gαq/Gα11, LARG) in vascular smooth muscle also normalized blood pressure.
- Normalization of blood pressure occurred despite persistent endothelial dysfunction.
Conclusions:
- Age-dependent elevation of blood pressure is attributed to reversible activation of procontractile signaling in vascular smooth muscle cells.
- Increased vascular tone, driven by these signaling pathways, can be a primary factor in hypertension development.
- Targeting vascular smooth muscle signaling pathways presents a potential therapeutic strategy for age-dependent hypertension.
Aims:
Arterial hypertension is a major risk factor for cardiovascular diseases. The kidney and its natriuretic function are in the centre of the prevailing models to explain the pathogenesis of hypertension; however, the mechanisms underlying blood pressure elevation remain unclear in most patients. Development of hypertension is strongly correlated with age, and this blood pressure increase typically accelerates in the fourth decade of life. The cause of age-dependent blood pressure elevation is poorly understood. This study aims to understand the role of procontractile G-protein-mediated signalling pathways in vascular smooth muscle in age-dependent hypertension.
Methods And Results:
Similar to humans at mid-life, we observed in 1-year-old mice elevated blood pressure levels without any evidence for increased vessel stiffness, impaired renal function, or endocrine abnormalities. Hypertensive aged mice showed signs of endothelial dysfunction and had an increased vascular formation of reactive oxygen species (ROS) and elevated endothelial ET-1 expression. Age-dependent hypertension could be normalized by ETA receptor blockade, smooth muscle-specific inactivation of the gene encoding the ETA receptor, as well as by acute disruption of downstream signalling via induction of smooth muscle-specific Gα12/Gα13, Gαq/Gα11, or LARG deficiency using tamoxifen-inducible smooth muscle-specific conditional mouse knock-out models. Induction of smooth muscle-specific ETA receptor deficiency normalized the blood pressure in aged mice despite the continuous presence of signs of endothelial dysfunction.
Conclusion:
Age-dependent blood pressure elevation is due to a highly reversible activation of procontractile signalling in vascular smooth muscle cells indicating that increased vascular tone can be a primary factor in the development of hypertension.
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