The Mechano-Immune-Vascular Activation Loop: An Integrative Conceptual Framework for Positive Feedback in...

Hypertension is increasingly recognized as involving chronic inflammation beyond its hemodynamic origins. This review proposes the Mechano-Immune-Vascular Activation Loop as an integrative conceptual framework-a positive feedback circuit in which aberrant mechanical forces in the hypertensive vascular wall may activate immune cells through mechanosensitive sensors, potentially triggering inflammation that drives vascular stiffening and amplifies mechanical stress. We examine molecular force sensors including piezo-type mechanosensitive ion channel component 1 (Piezo1), transient receptor potential vanilloid 4 (TRPV4), integrins, and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), detailing their expression in vascular cells and immune subsets such as T cells, macrophages, dendritic cells(DCs), and neutrophils. Downstream pathways-calcium-nuclear factor of activated T cells (Ca²⁺-NFAT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and Hippo-transduce physical stimuli into inflammatory gene programs. Organ-specific manifestations in the kidney, arteries, heart, and brain are discussed. Therapeutic approaches targeting mechanosensitive channels, repurposed antihypertensives, and mechanical environment modification are evaluated, along with challenges including off-target effects, pathway redundancy, and biomarker needs. By centering mechanotransduction in immune-vascular crosstalk, this framework offers new perspectives on hypertension pathogenesis and points toward interventions that may break the vicious cycle beyond conventional blood pressure reduction.