Vascular dysfunction orchestrates fibrotic progression in multiple organs: from mechanism decoding to therapeutic roadmap

Abstract Fibrosis is a leading cause of mortality across numerous diseases with limited treatment options. It is characterized by fibroblast overactivation typically resulting from chronic inflammation. While emerging research suggests a critical involvement of pathological vessels in regulating both inflammation and fibroblast activation, thereby linking vascular dysfunction to fibrogenesis, their precise mechanisms remain fragmented. Herein, we comprehensively review emerging evidence to establish a systematic framework of vascular regulation of fibrotic progression. We argue that aberrant vessels arise when endothelial cells (ECs) fail to regain quiescence under chronic stress and instead enter a dysfunctional state. We identify recurrently observed vascular remodeling modes, including capillary de-specialization, abortive angiogenesis, and venous encroachment, which impair oxygen delivery and create a hypoxic microenvironment that remodels cellular behavior and fuels fibrogenesis. Beyond these effects, we emphasize that disrupted angiocrine signaling can subvert the cellular communication network within the vascular niche, shifting it toward a pro-fibrotic state. Furthermore, we integrate systemic concepts of vascular aging to explain the persistent mismatch between vascular function and tissue demand. Collectively, these insights support the hypothesis that pathological vessels may act as context-dependent orchestrators of fibrotic progression. They also advocate for a shift toward precision vascular refunctionalization, which may provide a new roadmap for next-generation anti-fibrotic therapies.