Integrated Stress Response (ISR) Modulators in Vascular Diseases

Area of Science:

• Vascular Biology
• Molecular Mechanisms
• Signaling Networks

Background:

• Vascular dysfunction drives cardiovascular diseases, the leading cause of death globally.
• Limited therapeutic options stem from an incomplete understanding of vascular pathology mechanisms.
• The integrated stress response (ISR) is an understudied signaling network in vascular biology.

Purpose of the Study:

• To review the roles of core ISR kinases (PERK, GCN2, HRI, PKR) in vascular homeostasis and pathology.
• To present a framework for the ISR as a context-dependent "double-edged sword" in vascular diseases.
• To discuss pharmacological ISR modulators and their therapeutic potential.

Main Methods:

• Review of existing literature on ISR kinases in vascular biology.
• Analysis of ISR roles in atherosclerosis, pulmonary hypertension, and angiogenesis.
• Discussion of pharmacological modulators and preclinical findings.

Main Results:

• ISR kinases have dual roles: PERK and PKR promote inflammation and apoptosis, while GCN2 is protective.
• ISR outcomes depend on cell type, stress, and downstream signaling bias (ATF4 vs. CHOP).
• Pharmacological ISR modulators show promise in preclinical models by reducing inflammation and apoptosis.

Conclusions:

• The ISR is a critical regulatory node in vascular pathophysiology.
• Selective, context-aware modulation of the ISR is a potential therapeutic strategy for vascular diseases.
• Targeting the ISR may offer novel treatments for atherosclerosis, pulmonary hypertension, and other cardiovascular conditions.