Spatially Characterized Aortic Proteome Reveals Novel Regional Signatures and Glucocorticoid Receptor/Dipeptidase 1 Axis in Diabetic Vasculopathy

ABSTRACT Diabetes mellitus poses a major global health burden and is intricately linked to cardiovascular complications, yet the spatial molecular landscape of diabetic vasculopathy remains poorly defined. Since thoracic and abdominal aortas differ in embryological origin and hemodynamic microenvironments, we applied laser‐capture microdissection to map their spatial proteomes in health and diabetes, using a multidimensional framework across longitudinal (region) and transverse (disease) axes. This approach uncovered region‐specific protein and pathway signatures obscured by conventional bulk analyses, highlighting spatial heterogeneity in transcriptional regulators and flow‐sensitive proteins. We identified dipeptidase 1 (DPEP1), a membrane‐bound zinc metalloprotease, as selectively upregulated in the diabetic thoracic aorta and inducible by diabetic conditions and shear stress. Mechanistically, laminar shear stress promoted glucocorticoid receptor (GR) nuclear translocation to drive a GR/DPEP1 axis, potentially explaining region‐specific DPEP1 induction and its synergy with diabetic conditions. Functionally, chronic Dpep1 inhibition by cilastatin and endothelium‐specific Dpep1 knockdown attenuated neutrophilic vascular inflammation and rescued endothelial dysfunction in diabetic mice. Furthermore, the corticosteroid dexamethasone activated the shear stress‐responsive GR/DPEP1 axis in vivo, yet exerted time‐dependent vascular effects—acutely dampening neutrophilic inflammation, but chronically worsening hyperglycemia and aggravating vascular dysfunction. These findings reveal spatially defined biomarkers and highlight DPEP1 as a therapeutic target in diabetic vasculopathy.