Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype

作者：Timo Rademakers, Marco Manca, Han Jin, Tanguy Orban, Ljubica Perisic, Hubertus J. M. Frissen, Frank Rühle, Petra Hautvast, Jos van Rijssel, Kim van Kuijk, Barend Mees, Carine J. Peutz‐Kootstra, Sylvia Heeneman, Mat J.A.P. Daemen, Gerard Pasterkamp, Monika Stoll, Marc A. M. J. van Zandvoort, Ulf Hedin, Samuel Dequiedt, Jaap D. van Buul, Judith C. Sluimer, Erik A.L. Biessen · 发表于：Angiogenesis · 年份：2024 · DOI：10.1007/s10456-024-09921-z · 被引用次数：11 · 研究领域：Hippo pathway signaling and YAP/TAZ、Caveolin-1 and cellular processes、Cell Adhesion Molecules Research

The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating ...