Vascular Homeostasis in Suicidal Behavior: From Molecular Mechanisms to Clinical Implications

Suicidal behaviors (SBs) remain a major global health challenge, reflecting persistent gaps in understanding their neurobiological underpinnings. The scarcity of validated biological markers for diagnosis, prediction, or treatment response impedes clinical progress. Emerging evidence implicates vascular dysregulation as a contributing factor in the pathophysiology of SBs. In this review, we critically synthesize findings from clinical and preclinical studies to explore how disruptions in vascular homeostasis, including endothelial integrity, blood-brain barrier (BBB) permeability, platelet function, and microvascular flow, are associated with SB and related phenotypes. Epidemiological and genetic data further highlight shared vulnerability between SBs and cardiovascular or neurovascular conditions. Additionally, individuals with SBs exhibit signs of increased BBB permeability, platelet activation, nitric oxide dysregulation, altered kynurenine metabolism, elevated MMP-9 activity, and white matter hyperintensities. These vascular disturbances may promote a proinflammatory and oxidative environment that impairs neuroplasticity, thereby heightening vulnerability to SBs through cognitive and emotional dysregulation. Emerging molecular indicators of vascular dysfunction, such as claudin-5, thrombospondins, platelet-derived growth factors, and components of the nitric oxide system, have shown potential for improving diagnosis and guiding therapeutic development, although further replication is needed. While the current evidence remains preliminary and subject to limitations discussed herein, vascular dysfunction may serve as a dynamic indicator of both acute suicide risk and longer-term susceptibility. This review integrates vascular homeostasis into the broader biological framework of SBs, alongside stress-response pathways, inflammation, and neural dysfunction, offering novel insights into SB pathophysiology and paving the way for developing targeted diagnostic tools and interventions.