Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation

Area of Science:

• Cardiovascular Physiology
• Developmental Biology
• Endothelial Function

Background:

• The endothelium regulates vascular homeostasis via endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH).
• An imbalance in EDH:EDRF signaling is implicated in cardiovascular diseases.
• Developmental exposure to adverse conditions, such as a maternal high-fat diet, may predispose offspring to hypertension and vascular dysfunction.

Purpose of the Study:

• To investigate the impact of developmental conditioning via maternal high-fat diet on EDH:EDRF signaling pathways in adult male mice offspring.
• To determine if early-life dietary insults affect endothelial function and vascular reactivity later in life.

Main Methods:

• Mice offspring were exposed to control or high-fat (HF) diets during gestation and/or lactation.
• Cremaster arterioles and mesenteric arteries were studied in adult male offspring from four dietary groups: C/C, HF/C, C/HF, and HF/HF.
• Endothelium-dependent relaxation, specifically EDH-mediated responses via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels, was assessed.

Main Results:

• EDH contributed significantly less to acetylcholine-induced relaxation in HF/C offspring compared to controls (∼10% vs. ∼60%).
• This reduction in EDH signaling was reversed in HF/HF offspring, indicating a restoration of function with continued high-fat exposure.
• Changes in EDH:EDRF signaling correlated with altered endothelial IKCa channel expression and localization.

Conclusions:

• Maternal high-fat diet exposure adversely affects EDH-mediated microvascular relaxation by down-regulating IKCa signaling.
• This study provides the first evidence linking developmental environment to EDH pathway susceptibility.
• Exposure to a 'second hit' of high-fat diet (HF/HF) appears to induce adaptive vascular mechanisms that preserve endothelial dilator function.