# Integrated Stress Response (ISR) Modulators in Vascular Diseases

## TL;DR

The integrated stress response (ISR) plays a key role in vascular diseases, with some components causing harm and others offering protection, suggesting potential for targeted therapies.

## Contribution

This paper provides a conceptual framework for the dual roles of ISR kinases in vascular health and disease, emphasizing the need for context-aware therapeutic modulation.

## Key findings

- PERK and PKR signaling pathways drive maladaptive vascular remodeling and inflammation under chronic stress.
- GCN2 exerts protective effects, especially in the pulmonary circulation.
- Pharmacological modulators of ISR show promise in preclinical models of vascular diseases.

## Abstract

What are the main findings?
The integrated stress response (ISR) has emerged as an important regulator of vascular homeostasis and pathology, orchestrating endothelial adaptation to metabolic, oxidative, and inflammatory stress through coordinated translational and transcriptional control.PERK and PKR signaling pathways promote maladaptive vascular remodeling under chronic stress, driving endothelial apoptosis, inflammation, and pathological neovascularization, whereas GCN2 exerts protective effects, particularly in the pulmonary circulation.

The integrated stress response (ISR) has emerged as an important regulator of vascular homeostasis and pathology, orchestrating endothelial adaptation to metabolic, oxidative, and inflammatory stress through coordinated translational and transcriptional control.

PERK and PKR signaling pathways promote maladaptive vascular remodeling under chronic stress, driving endothelial apoptosis, inflammation, and pathological neovascularization, whereas GCN2 exerts protective effects, particularly in the pulmonary circulation.

What are the implications of the main findings?
Selective pharmacological targeting of ISR components offers therapeutic promise, with both inhibitors (e.g., GSK2606414, 2-aminopurine, C16) and activators (e.g., salubrinal, halofuginone) demonstrating efficacy in preclinical models of atherosclerosis, restenosis, thrombosis, and pulmonary hypertension.The dual and context-dependent roles of ISR signaling underscore the need for precision-targeted modulation, with therapeutic outcomes varying by disease state, cellular context, and the specific ISR kinase engaged.Translational progress is currently limited by gaps in pharmacokinetics, selectivity, and long-term safety profiles of ISR modulators, highlighting the necessity for mechanistic dissection and in vivo validation to support clinical application.

Selective pharmacological targeting of ISR components offers therapeutic promise, with both inhibitors (e.g., GSK2606414, 2-aminopurine, C16) and activators (e.g., salubrinal, halofuginone) demonstrating efficacy in preclinical models of atherosclerosis, restenosis, thrombosis, and pulmonary hypertension.

The dual and context-dependent roles of ISR signaling underscore the need for precision-targeted modulation, with therapeutic outcomes varying by disease state, cellular context, and the specific ISR kinase engaged.

Translational progress is currently limited by gaps in pharmacokinetics, selectivity, and long-term safety profiles of ISR modulators, highlighting the necessity for mechanistic dissection and in vivo validation to support clinical application.

Vascular dysfunction lies at the core of cardiovascular diseases—the leading cause of global morbidity and mortality. Despite their prevalence, therapeutic options remain limited, in part due to an incomplete understanding of the molecular mechanisms driving vascular pathology. The integrated stress response (ISR), an evolutionarily conserved signaling network activated by diverse stressors, represents a critical but underexplored mechanism in vascular biology. This review examines the dual roles of the core ISR kinases—PERK, GCN2, HRI and PKR—in vascular homeostasis and pathology, including atherosclerosis, pulmonary hypertension, and angiogenesis. We develop a conceptual framework in which the ISR functions as a context-dependent, double-edged sword: while PERK and PKR promote inflammation, apoptosis, and vascular re-modeling, GCN2 mediates protective effects. The outcome of ISR activation is shaped by cell type, stress duration and intensity, and downstream signaling bias (e.g., ATF4 vs. CHOP dominance). We further discuss pharmacological ISR modulators—including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157—which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention.