Bryostatin-1 improves function in arteries with suppressed endothelial cell autophagy

Area of Science:

• Endothelial cell biology
• Vascular physiology
• Autophagy research

Background:

• Endothelial cell (EC) autophagy impairment compromises nitric oxide (NO) production and vascular function.
• This impairment is linked to defective ATP production and purinergic receptor signaling.
• Protein kinase C delta (PKCδ) acts as a signaling intermediate between receptor activation and NO generation.

Purpose of the Study:

• To investigate the functional relevance of PKCδ in EC autophagy-compromised conditions.
• To determine if stimulating PKC can restore endothelial function in models of autophagy deficiency.
• To elucidate the downstream signaling pathways involved in this restoration.

Main Methods:

• Utilized knockdown of autophagy-related gene 3 (Atg3) in ECs.
• Administered the PKC agonist bryostatin-1 to ECs and murine models.
• Assessed shear-stress-induced phosphorylation of endothelial nitric oxide synthase (eNOS).
• Measured vasodilation in femoral and cerebral arteries of murine models.
• Investigated the role of downstream PKC/PKD signaling pathways.

Main Results:

• Bryostatin-1 restored shear-stress-induced eNOS phosphorylation in Atg3-knockdown ECs.
• Bryostatin-1 reversed depressed vasodilation in arteries from genetic and aged EC autophagy-compromised mice.
• NO synthase inhibition prevented the vasodilatory effects of bryostatin-1.
• Inhibition of downstream PKC/PKD targets (p-PKD^S744/S748 and p-PKD^S916) mitigated bryostatin-1's normalizing effect on vasodilation.

Conclusions:

• PKC/PKD stimulation strategically restores compromised endothelial function in pathologies with suppressed EC autophagy, such as aging.
• Targeting PKC/PKD pathways presents a potential therapeutic approach for age-related vascular dysfunction.
• This study highlights the critical role of autophagy in maintaining endothelial nitric oxide production and vascular health.