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

Chak Kwong Cheng; Shuhui Meng; Teng Li; Huanyu Ding; Minchun Jiang; Zizhao Tian; Chi-Fai Ng; Yin Xia; Stefan Offermanns; Yu Huang

doi:10.1002/mco2.70714

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

Chak Kwong Cheng^*
, Shuhui Meng
, Teng Li
, Huanyu Ding
, Minchun Jiang
, Zizhao Tian
, Chi-Fai Ng
, Yin Xia
, Stefan Offermanns
, Yu Huang^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

1 Citation (Scopus)

3 Downloads (CityUHK Scholars)

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. © 2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

Original language	English
Article number	e70714
Number of pages	22
Journal	MedComm
Volume	7
Issue number	4
Online published	30 Mar 2026
DOIs	https://doi.org/10.1002/mco2.70714
Publication status	Published - Apr 2026

Funding

This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, China (T12-101/23-N, RGC-SRFS2021-4S04) and the City University of Hong Kong Start-Up Fund. This work was also substantially supported by a fellowship award from the Research Grants Council of the Hong Kong Special Administrative Region, China (project No. CityU PDFS2223-1S01) and the fellowship scheme funded by William G. Kerckhoff Foundation. The authors thank the members of the Yu Huang group for the constructive discussion and critical comments. Some figure panels were created with BioRender.com. During the preparation of this manuscript, the authors used Deepseek-V3.2 to assist with grammar correction and enhance readability. Following its use, all content was thoroughly reviewed and edited as needed by the authors, who take complete responsibility for the work as presented.

Research Keywords

diabetes
endothelial function
inflammation
proteomics
shear stress
vasculopathy

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

RGC Funding Information

RGC-funded

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@article{e861a380e9a64ec29e833a99220ca627,

title = "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. {\textcopyright} 2026 The Author(s). MedComm published by Sichuan International Medical Exchange \& Promotion Association (SCIMEA) and John Wiley \& Sons Australia, Ltd.",

keywords = "diabetes, endothelial function, inflammation, proteomics, shear stress, vasculopathy",

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TY - JOUR

T1 - Spatially Characterized Aortic Proteome Reveals Novel Regional Signatures and Glucocorticoid Receptor/Dipeptidase 1 Axis in Diabetic Vasculopathy

AU - Cheng, Chak Kwong

AU - Meng, Shuhui

AU - Li, Teng

AU - Ding, Huanyu

AU - Jiang, Minchun

AU - Tian, Zizhao

AU - Ng, Chi-Fai

AU - Xia, Yin

AU - Offermanns, Stefan

AU - Huang, Yu

PY - 2026/4

Y1 - 2026/4

N2 - 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. © 2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

AB - 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. © 2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

KW - diabetes

KW - endothelial function

KW - inflammation

KW - proteomics

KW - shear stress

KW - vasculopathy

UR - https://www.scopus.com/pages/publications/105034591605

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105034591605&origin=recordpage

U2 - 10.1002/mco2.70714

DO - 10.1002/mco2.70714

M3 - RGC 21 - Publication in refereed journal

SN - 2688-2663

VL - 7

JO - MedComm

JF - MedComm

IS - 4

M1 - e70714

ER -

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

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TBRS-Sub-pj: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

TBRS-Sub-pj: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

TBRS-Sub-pj: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

Cite this

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

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

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TBRS-Sub-pj: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

TBRS-Sub-pj: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

TBRS-Sub-pj: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

Cite this