Endothelial calreticulin deletion impairs endothelial function in aged mice.

Area of Science:

• Vascular Biology
• Endocrinology
• Cellular Physiology

Background:

• Endothelial calcium signaling declines with age, impacting vasodilation.
• Calreticulin (Calr), an ER calcium-binding protein, is vital for endothelial cell function.
• Age-related decrease in Calr expression is observed in mesenteric arteries.

Purpose of the Study:

• To investigate the functional role of endothelial Calr in age-related vascular dysfunction.
• To determine if EC Calr deficiency impairs vasodilation and calcium signaling in aged mice.
• To assess the potential of ER stress inhibition to rescue impaired vasodilation.

Main Methods:

• Generated mice with endothelial cell-specific Calr knockdown.
• Aged mice to 75 weeks.
• Measured vascular responses (constriction/vasodilation) and intracellular calcium signals in mesenteric arteries.
• Treated arteries ex vivo with tauroursodeoxycholic acid (TUDCA).

Main Results:

• Endothelial Calr knockdown in aged mice significantly impaired carbachol-induced vasodilation and calcium signals.
• Phenylephrine-induced constriction was unaffected by EC Calr knockdown in aged mice.
• TUDCA treatment rescued the impaired vasodilation in aged mice lacking EC Calr.

Conclusions:

• Diminished endothelial Calr expression contributes to impaired endothelial-dependent vasodilation in aging.
• Targeting ER stress with TUDCA may offer a therapeutic strategy for age-related vascular dysfunction.
• Endothelial Calr is critical for maintaining vascular function during aging.