Renin-Angiotensin Signaling and Vascular Function: Insights into Health and Disease

The renin-angiotensin system (RAS) is an essential regulator of vascular structure and function, and dysregulation of angiotensin II (Ang II) signaling plays a critical role in the development of hypertension and associated vascular complications. Ang II exerts its vascular actions primarily through the angiotensin II type 1 receptor (AT1R), activating canonical and non-canonical signaling pathways that extend beyond classical G-protein-dependent signaling mechanisms. Here, we review the literature on tissue-specific RAS, Ang II-dependent and Ang II-independent signaling mechanisms of vascular Ang II receptors, and their contribution to vasoconstriction, endothelial dysfunction, vascular remodeling, and arterial stiffness in hypertension. We highlight the roles of mechanosensitive AT1R signaling, dysregulation of vascular ion channels, enhanced reactive oxygen species production, immune and inflammatory signaling, and mineralocorticoid receptor activation as key drivers of hypertensive vascular pathology. In addition, we discuss tissue-specific expression of RAS components and separation between RAS pathways underlying blood pressure elevation and vascular remodeling in hypertension. Collectively, emerging research on vascular Ang II receptor signaling reveals novel regulatory mechanisms and therapeutic opportunities beyond conventional RAS inhibition. Targeting downstream pathways that mediate oxidative stress, mechanotransduction, ion channel activity, and profibrotic signaling may offer improved strategies to prevent or reverse Ang II receptor-dependent vascular dysfunction in hypertension.