The RhoA/ROCK pathway in vascular dysfunction and inflammation: Mechanisms and therapeutic targeting

Abstract

Cardiovascular diseases (CVDs) remain the foremost global cause of mortality, largely driven by endothelial dysfunction and vascular remodelling. The RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signalling pathway is central to vascular homeostasis, regulating vascular smooth muscle cell (VSMC) phenotypic plasticity, contraction, nitric oxide (NO) bioavailability, and cytoskeletal organization. Aberrant RhoA/ROCK activation contributes to hypertension, atherosclerosis, heart failure, and vascular stiffness through impaired endothelial function, oxidative stress, and maladaptive remodelling. This narrative review summarises current evidence on molecular mechanisms linking RhoA/ROCK activity with endothelial dysfunction and vascular pathology, highlighting its crosstalk with phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt), reactive oxygen species (ROS), and inflammatory mediators. Therapeutic insights focus on ROCK inhibitors, particularly fasudil, their limitations in isoform selectivity, and recent advances in structure-based drug design and targeted delivery systems. Isoform-specific and next-generation inhibitors represent a new frontier in therapy, with the potential to precisely suppress pathogenic RhoA/ROCK-driven inflammation, restore endothelial function, and markedly diminish cardiovascular disease burden.