Complement C3 in panvascular disease: a central integrator of immune signaling and vascular remodeling

Panvascular disease, defined by the systemic involvement of multiple vascular beds, poses a growing challenge to contemporary diagnostic and therapeutic paradigms. Despite organ-specific manifestations, these conditions share a convergent pathological basis driven by chronic low-grade inflammation, immune dysregulation, and maladaptive vascular remodeling. Within this immunovascular interface, complement C3 (C3) has emerged as a pivotal regulator. Positioned at the convergence of the classical, lectin, and alternative complement pathways, C3 integrates systemic immune cues with microenvironmental stimuli to orchestrate endothelial activation, smooth muscle cell phenotypic switching, immune cell recruitment, platelet activation, and fibroinflammatory remodeling. This review provides a comprehensive analysis of C3 biology, including its structural domains, activation cascades, and downstream effector functions. We examine the role of C3 across major vascular cell types, endothelial cells, vascular smooth muscle cells, innate and adaptive immune cells, platelets, and fibroblasts, highlighting how C3 signaling dynamically shapes both acute injury responses and chronic vascular adaptation. In disease-specific contexts, we delineate how C3 contributes to the pathogenesis of atherosclerosis, coronary artery disease, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, peripheral vascular disease, stroke, and autoimmune- associated vasculitides. Special emphasis is placed on the dual-phase roles of C3, such as its injuryexacerbating effects in the acute phase of stroke versus its reparative functions in neuroregeneration. Finally, we review emerging therapeutic strategies targeting C3, with a focus on compstatin-based inhibitors, their pharmacological profiles, clinical trial progress, and immunological safety considerations. Collectively, this review reframes C3 as a master orchestrator of panvascular pathology and a promising target for precision immunomodulation across vascular systems.