Age Impairs Soluble Guanylyl Cyclase Function in Mouse Mesenteric Arteries

Area of Science:

• Vascular Biology
• Aging Research
• Cardiovascular Physiology

Background:

• Endothelial dysfunction (ED) is a hallmark of aging, often preceding overt vascular diseases.
• The impact of aging on the nitric oxide (NO) signaling pathway within vascular smooth muscle (VSM) requires further investigation.

Purpose of the Study:

• To investigate how aging affects downstream signaling of the endothelial nitric oxide (NO) system in VSM.
• To determine the role of soluble guanylyl cyclase (sGC) and phosphodiesterase type 5 (PDE5) in age-related vascular dysfunction.

Main Methods:

• Isometric wire myography was used to assess vasorelaxation in mesenteric arteries from juvenile (13-week) and aged (40-week) mice.
• Responses to acetylcholine (ACh), sodium nitroprusside (SNP), and runcaciguat were measured.
• cGMP concentrations and PDE5 inhibitor effects were analyzed.
• mRNA expression of sGC subunits and PDE5 was quantified.

Main Results:

• Aged vessels showed reduced acetylcholine-induced relaxation compared to juvenile vessels.
• Nitric oxide synthase inhibition (L-NAME) abolished age-related differences in ACh-mediated relaxation.
• While endothelium-independent relaxation to SNP was similar, juvenile vessels exhibited faster responses to SNP and runcaciguat, with higher cGMP levels.
• Aged vessels had lower mRNA expression of sGC subunits (α1, α2) and PDE5.
• No significant histological differences were observed between groups.

Conclusions:

• Vascular smooth muscle (VSM) vasorelaxation is compromised with age in mice, even in the absence of histopathological changes.
• Reduced soluble guanylyl cyclase (sGC) signaling in VSM is a critical factor in age-related vascular dysfunction.
• Targeting the sGC pathway may offer therapeutic potential for age-associated endothelial dysfunction.