PARP7 drives angiotensin II-induced vascular remodeling via ADP-ribosylation and inhibition of GPX4.

Pathological vascular remodeling is driven by metabolic imbalance in vascular smooth muscle cells (VSMCs). NAD+ homeostasis is essential for sustaining VSMC contractility, quiescence, and genomic stability. ADP-ribosylation, catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes, is an NAD+-dependent modification that links NAD+ consumption to cellular stress. Here, we identify the mono-ADP-ribosyltransferase PARP7 as a critical regulator of vascular remodeling, with elevated expression in VSMCs. Parp7 deficiency attenuates angiotensin II-induced remodeling, while VSMC-specific overexpression exacerbates it. Mechanistically, PARP7 binds GPX4 via its WWE domain, and GPX4 mono-ADP-ribosylation depends on the catalytic activity of H532 in PARP7. This modification suppresses GPX4 activity and promotes VSMC ferroptosis. These findings establish a VSMC-specific PARP7-GPX4 axis in vascular remodeling and highlight PARP7 as a potential therapeutic target in hypertensive vascular disease.