Beyond the guidelines: Vascular function as the central determinant and therapeutic target in hypertension.

Hypertension has traditionally been defined and managed according to brachial blood pressure levels. Although this pressure-centric strategy has significantly reduced cardiovascular morbidity and mortality, substantial residual risk persists even among patients who achieve recommended blood pressure targets. Emerging evidence indicates that hypertension is fundamentally a systemic disorder of the vascular wall, in which endothelial dysfunction, oxidative stress, immune activation, microvascular remodeling, and progressive arterial stiffening not only result from elevated pressure but also actively drive its initiation and progression. Endothelial nitric oxide deficiency, redox imbalance with endothelial nitric oxide synthase uncoupling, T helper 17 cell-mediated inflammation, and mineralocorticoid receptor-dependent vascular signaling collectively promote increased vascular tone and structural remodeling. Microvascular rarefaction elevates peripheral resistance, while large-artery stiffening augments central pulsatile load and accelerates target organ injury. These interconnected processes create a self-reinforcing network that sustains hypertension beyond simple hemodynamic elevation. In this review, I propose a shift from a pressure-centric to a vessel-centric paradigm of hypertension. I describe mechanistically defined vascular phenotypes, discuss macrovascular and microvascular assessment strategies, and explore therapeutic approaches aimed at vascular restoration in addition to blood pressure reduction. I further examine the concepts of vascular age, residual risk, and precision vascular medicine, and consider future integration of artificial intelligence and vascular endpoints into clinical trials. Recognizing vascular dysfunction as a central determinant of hypertension may refine risk stratification, redefine therapeutic success, and represent the next frontier in cardiovascular medicine. Beyond Blood Pressure: Vascular Function as the Central Determinant and Therapeutic Target in Hypertension. FMD indicates flow-mediated vasodilation, RHI reactive hyperemia index, cFPWV carotid-femoral pulse wave velocity, baPWV brachial-ankle PWV, CAVI cardio ankle vascular index, Nox nitrite/nitrate, ADMA asymmeteric dimethylarginen, RAAS renin-angiotensin-aldosterone system, SGLT2 sodium-glucose cotransporter 2, NO nitric oxide.