Deep vein thrombosis exacerbated by syndecan-4 shedding and piezo1-dependent endothelial-mesenchymal transition

Deep vein thrombosis (DVT) remains a major health burden with incompletely understood mechanisms and limited therapeutic options. This study aims to investigate the role of key molecules in DVT and to explore the feasibility of treatment strategies based on this mechanism.

Plasma proteomic profiling (LC-MS/MS) was performed on DVT patients and healthy controls, identifying syndecan-4 (SDC4) as a differentially expressed protein. Functional investigations utilized SDC4 knockout mice, endothelial cell (EC)-specific lineage tracing models, and single-cell RNA sequencing to assess endothelial-to-mesenchymal transition (EndMT) during DVT progression. In vitro EndMT models were established in human umbilical vein endothelial cells. Protein interactions were confirmed by co-immunoprecipitation. Piezo1 was pharmacologically inhibited in vivo, and network pharmacology was used to seek a potential therapeutic agent.

SDC4 levels were elevated in DVT patients. SDC4 deficiency exacerbated thrombus formation and promoted EndMT, as evidenced by reduced EC markers and increased mesenchymal markers. Single-cell sequencing revealed a specific EC subpopulation (C1) driving EndMT, with Piezo1 identified as a downstream mediator of SDC4. Co-IP confirmed direct SDC4-Piezo1 interaction. Piezo1 upregulation activated the PI3K/Akt pathway, Piezo1 knockdown attenuated EndMT and reduced thrombus burden. Quercetin directly bound Piezo1, reduced its expression in a dose-dependent manner, and significantly decreased thrombus size in DVT mice.

SDC4 shedding exacerbates DVT by promoting Piezo1-dependent EndMT via PI3K/Akt signalling. Quercetin shows therapeutic potential as a Piezo1 inhibitor.