Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins
Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remod...
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MDPI AG
2021-12-01
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| author | Karthika Chandran Latha Ahalya Sreekumar Vyshna Beena Binil Raj S.S. RaviKumar B. Lakkappa Ravi Kalyani Radhakrishnan Nair Saligrama Ramegowda Kalpana Chandrasekharan C. Kartha Sumi Surendran |
| author_facet | Karthika Chandran Latha Ahalya Sreekumar Vyshna Beena Binil Raj S.S. RaviKumar B. Lakkappa Ravi Kalyani Radhakrishnan Nair Saligrama Ramegowda Kalpana Chandrasekharan C. Kartha Sumi Surendran |
| author_sort | Karthika Chandran Latha |
| collection | DOAJ |
| description | Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFβ inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins <i>via</i> activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins. |
| first_indexed | 2024-03-10T04:25:16Z |
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| language | English |
| last_indexed | 2024-03-10T04:25:16Z |
| publishDate | 2021-12-01 |
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| series | Cells |
| spelling | doaj.art-e31c3014808c4a1fb6caaff284fbbda62023-11-23T07:39:32ZengMDPI AGCells2073-44092021-12-011012356310.3390/cells10123563Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose VeinsKarthika Chandran Latha0Ahalya Sreekumar1Vyshna Beena2Binil Raj S.S.3RaviKumar B. Lakkappa4Ravi Kalyani5Radhakrishnan Nair6Saligrama Ramegowda Kalpana7Chandrasekharan C. Kartha8Sumi Surendran9Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, IndiaCardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, IndiaCardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, IndiaCollege of Pharmaceutical Sciences, Medical College, Thiruvananthapuram 695011, IndiaVascular Surgery, Kempegowda Institute of Medical Sciences, Bangalore 560070, IndiaSri Jayadeva Institute for Cardiovascular Sciences & Research, Bangalore 560069, IndiaSt. Thomas Institute of Research on Venous Diseases, Changanassery 686104, IndiaSri Jayadeva Institute for Cardiovascular Sciences & Research, Bangalore 560069, IndiaDepartment of Neurology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi 682041, IndiaCardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, IndiaChronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFβ inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins <i>via</i> activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins.https://www.mdpi.com/2073-4409/10/12/3563varicose veinsshear stressendothelial cellsEndMTTGFβBMP |
| spellingShingle | Karthika Chandran Latha Ahalya Sreekumar Vyshna Beena Binil Raj S.S. RaviKumar B. Lakkappa Ravi Kalyani Radhakrishnan Nair Saligrama Ramegowda Kalpana Chandrasekharan C. Kartha Sumi Surendran Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins Cells varicose veins shear stress endothelial cells EndMT TGFβ BMP |
| title | Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins |
| title_full | Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins |
| title_fullStr | Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins |
| title_full_unstemmed | Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins |
| title_short | Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins |
| title_sort | shear stress alterations activate bmp4 psmad5 signaling and induce endothelial mesenchymal transition in varicose veins |
| topic | varicose veins shear stress endothelial cells EndMT TGFβ BMP |
| url | https://www.mdpi.com/2073-4409/10/12/3563 |
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