Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction
ABSTRACT Sudomotor dysfunction in diabetic patients increases the risk of fissures, infections, and diabetic foot ulcers (DFUs), thereby reducing the quality of life. Despite its clinical importance, the mechanisms underlying this dysfunction remain inadequately elucidated. This study addresses this...
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Wiley
2025-05-01
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| Online Access: | https://doi.org/10.1002/mco2.70173 |
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| author | Xu Guo Chao Zhang Yuzhen Wang Zhao Li Yaxin Tan Dongzhen Zhu Wei Song Yi Kong Jinpeng Du Yuyan Huang Liting Liang Jianjun Li Mengde Zhang Linhao Hou Qinhua Liu Feng Tian Bingyang Yu Yue Kong Zhenyu Zhou Xiaobing Fu Sha Huang |
| author_facet | Xu Guo Chao Zhang Yuzhen Wang Zhao Li Yaxin Tan Dongzhen Zhu Wei Song Yi Kong Jinpeng Du Yuyan Huang Liting Liang Jianjun Li Mengde Zhang Linhao Hou Qinhua Liu Feng Tian Bingyang Yu Yue Kong Zhenyu Zhou Xiaobing Fu Sha Huang |
| author_sort | Xu Guo |
| collection | DOAJ |
| description | ABSTRACT Sudomotor dysfunction in diabetic patients increases the risk of fissures, infections, and diabetic foot ulcers (DFUs), thereby reducing the quality of life. Despite its clinical importance, the mechanisms underlying this dysfunction remain inadequately elucidated. This study addresses this gap by demonstrating that despite structural integrity, sweat glands (SGs) in diabetic individuals with DFUs, and a murine model of diabetic neuropathy (DN), exhibit functional impairments, as confirmed by histological and functional assays. Integrated transcriptome and proteome analysis revealed significant upregulation of the SG microenvironment in response to hypoxia, highlighting potential underlying pathways involved. In addition, histological staining and tissue clearing techniques provided evidence of impaired neurovascular networks adjacent to SGs. Single‐cell RNA sequencing unveiled intricate intercellular communication networks among endothelial cells (ECs), neural cells (NCs), and sweat gland cells (SGCs), emphasizing intricate cellular interactions within the SG microenvironment. Furthermore, an in vitro SGC–NC interaction model (SNIM) was employed to validate the supportive role of NCs in regulating SGC functions, highlighting the neurovascular‐SG axis in diabetic pathophysiology. These findings confirm the hypoxia‐driven upregulation of the SG microenvironment and underscore the critical role of the neurovascular‐SG axis in diabetic pathophysiology, providing insights into potential therapeutic targets for managing diabetic complications and improving patient outcomes. |
| format | Article |
| id | doaj-art-06b43cca12fb456986f1af2d949bf6c0 |
| institution | OA Journals |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-06b43cca12fb456986f1af2d949bf6c02025-08-20T02:32:12ZengWileyMedComm2688-26632025-05-0165n/an/a10.1002/mco2.70173Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor DysfunctionXu Guo0Chao Zhang1Yuzhen Wang2Zhao Li3Yaxin Tan4Dongzhen Zhu5Wei Song6Yi Kong7Jinpeng Du8Yuyan Huang9Liting Liang10Jianjun Li11Mengde Zhang12Linhao Hou13Qinhua Liu14Feng Tian15Bingyang Yu16Yue Kong17Zhenyu Zhou18Xiaobing Fu19Sha Huang20College of Graduate Tianjin Medical University Tianjin People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaCollege of Graduate Tianjin Medical University Tianjin People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaCollege of Graduate Tianjin Medical University Tianjin People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaDepartment of Orthopedics The 960th Hospital of the PLA Joint Logistics Support Force Jinan People's Republic of ChinaCollege of Graduate Tianjin Medical University Tianjin People's Republic of ChinaResearch Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department PLA General Hospital and PLA Medical College Beijing People's Republic of ChinaABSTRACT Sudomotor dysfunction in diabetic patients increases the risk of fissures, infections, and diabetic foot ulcers (DFUs), thereby reducing the quality of life. Despite its clinical importance, the mechanisms underlying this dysfunction remain inadequately elucidated. This study addresses this gap by demonstrating that despite structural integrity, sweat glands (SGs) in diabetic individuals with DFUs, and a murine model of diabetic neuropathy (DN), exhibit functional impairments, as confirmed by histological and functional assays. Integrated transcriptome and proteome analysis revealed significant upregulation of the SG microenvironment in response to hypoxia, highlighting potential underlying pathways involved. In addition, histological staining and tissue clearing techniques provided evidence of impaired neurovascular networks adjacent to SGs. Single‐cell RNA sequencing unveiled intricate intercellular communication networks among endothelial cells (ECs), neural cells (NCs), and sweat gland cells (SGCs), emphasizing intricate cellular interactions within the SG microenvironment. Furthermore, an in vitro SGC–NC interaction model (SNIM) was employed to validate the supportive role of NCs in regulating SGC functions, highlighting the neurovascular‐SG axis in diabetic pathophysiology. These findings confirm the hypoxia‐driven upregulation of the SG microenvironment and underscore the critical role of the neurovascular‐SG axis in diabetic pathophysiology, providing insights into potential therapeutic targets for managing diabetic complications and improving patient outcomes.https://doi.org/10.1002/mco2.70173neural supportneurovascular networksudomotor dysfunctionsweat gland cell–neural cell interaction modelsweat gland microenvironment |
| spellingShingle | Xu Guo Chao Zhang Yuzhen Wang Zhao Li Yaxin Tan Dongzhen Zhu Wei Song Yi Kong Jinpeng Du Yuyan Huang Liting Liang Jianjun Li Mengde Zhang Linhao Hou Qinhua Liu Feng Tian Bingyang Yu Yue Kong Zhenyu Zhou Xiaobing Fu Sha Huang Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction MedComm neural support neurovascular network sudomotor dysfunction sweat gland cell–neural cell interaction model sweat gland microenvironment |
| title | Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction |
| title_full | Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction |
| title_fullStr | Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction |
| title_full_unstemmed | Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction |
| title_short | Hypoxia‐Driven Neurovascular Impairment Underlies Structural‐Functional Dissociation in Diabetic Sudomotor Dysfunction |
| title_sort | hypoxia driven neurovascular impairment underlies structural functional dissociation in diabetic sudomotor dysfunction |
| topic | neural support neurovascular network sudomotor dysfunction sweat gland cell–neural cell interaction model sweat gland microenvironment |
| url | https://doi.org/10.1002/mco2.70173 |
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