CCR5/CCL5-Dependent Mitochondrial Dysfunction Contributes to Angiotensin II-Induced Vascular Impairment in Mice

Area of Science:

• Cardiovascular Research
• Vascular Biology
• Mitochondrial Medicine

Background:

• Chemokine signaling, specifically CCL5/CCR5, is implicated in vascular inflammation and dysfunction during hypertension.
• The precise intracellular mechanisms linking CCL5/CCR5 activation to vascular impairment are not fully understood.

Purpose of the Study:

• To investigate whether angiotensin II (Ang II) amplifies CCL5/CCR5 signaling.
• To determine if this amplified signaling promotes mitochondrial dysfunction and oxidative stress in the vasculature.

Main Methods:

• Utilized wild-type and CCR5-deficient mice subjected to Ang II infusion or CCL5 administration.
• Assessed vascular function and remodeling in aorta and mesenteric arteries.
• Evaluated mitochondrial respiration, membrane potential, and reactive oxygen species (ROS) production in vascular smooth muscle cells (VSMCs).

Main Results:

• Ang II increased circulating CCL5 and vascular CCR5 expression; CCR5 deficiency conferred protection against Ang II-induced vascular issues.
• CCL5 infusion alone impaired endothelial relaxation and increased contractility, disrupting mitochondrial respiration and increasing ROS in VSMCs.
• Mitochondrial antioxidant treatment partially restored endothelial function but not contractility, indicating impaired mitochondrial reserve.

Conclusions:

• Angiotensin II amplifies CCL5/CCR5 signaling, leading to mitochondrial dysfunction and oxidative stress.
• This pathway significantly contributes to vascular impairment in hypertension.
• The CCL5/CCR5-mitochondrial axis represents a potential therapeutic target for hypertension management.