Shear Stress Alterations Activate BMP4/pSMAD5 Signaling and Induce Endothelial Mesenchymal Transition in Varicose Veins

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 12; p. 3563
• Main Authors: Chandran Latha, Karthika, Sreekumar, Ahalya, Beena, Vyshna, S S, Binil Raj, Lakkappa, RaviKumar B, Kalyani, Ravi, Nair, Radhakrishnan, Kalpana, Saligrama Ramegowda, Kartha, Chandrasekharan C, Surendran, Sumi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.12.2021; MDPI
• Subjects: Adult; Aged; Antibodies; Biomarkers - metabolism; BMP; Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - metabolism; EndMT; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - pathology; Female; Gene expression; Gene Expression Profiling; Hemodynamics; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Male; Mesenchyme; Mesoderm - pathology; Middle Aged; Neointima - pathology; Phenotypes; Phosphorylation - drug effects; Proteins; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Rheology - drug effects; Shear stress; Signal transduction; Signal Transduction - drug effects; Smad5 Protein - metabolism; Small Molecule Libraries - pharmacology; Snail Family Transcription Factors - metabolism; Snail protein; Stress, Mechanical; Surgeons; TGFβ; Transforming Growth Factor beta1 - metabolism; Up-Regulation - drug effects; Varicose veins; Varicose Veins - metabolism; Varicose Veins - pathology; Young Adult; United States > US; Japan; TGFβ; endothelial cells; shear stress; BMP; EndMT; varicose veins
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10123563

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 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.