Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways

Area of Science:

• Vascular Biology
• Adipose Tissue Biology
• Cellular Metabolism

Background:

• Perivascular adipose tissue (PVAT) influences vascular function through secreted factors.
• Obesity activates Notch signaling in PVAT, causing adipocyte whitening and loss of thermogenic properties.
• Constitutive Notch activation in PVAT mimics obesity-related changes.

Purpose of the Study:

• To investigate the downstream molecular pathways affected by Notch signaling in PVAT.
• To elucidate the impact of Notch-induced PVAT dysfunction on mitochondrial function and ferroptosis.
• To determine the consequences of activated Notch signaling in PVAT on vascular reactivity.

Main Methods:

• Proteomic analysis of PVAT from control and Notch-activated mice (N1ICD;Adipoq-Cre).
• Assessment of mitochondrial respiration and adipogenesis in PVAT-derived stromal vascular fraction cells.
• Wire myography to evaluate vasoreactivity in aortae from experimental mice.

Main Results:

• Notch activation in PVAT altered protein signatures related to metabolism, adipocyte homeostasis, mitochondrial function, and ferroptosis.
• Activated Notch signaling reduced mitochondrial respiration in PVAT cells without affecting adipogenesis or mitochondrial number.
• Notch activation promoted lipid peroxidation and ferroptosis in PVAT adipocytes, leading to increased vasocontraction and decreased vasorelaxation in aortae.

Conclusions:

• Increased Notch signaling in adipose tissue drives PVAT whitening, mitochondrial dysfunction, and ferroptosis.
• These PVAT changes result in impaired vascular protective signals and altered vasoreactivity.
• The study highlights a novel link between adipocyte Notch signaling, mitochondrial dynamics, and vascular physiology.