Plenary 1 Monday 31 May – Session 1

New phenotypes for stratification and modelling of atherosclerosis: Gerard Pasterkamp, Utrecht, The Netherlands

Atherosclerosis: metabolism dysfunction drives inflammation in the vessels

Gerard Pasterkamp is Professor of Experimental Cardiology and Scientific Medical Manager of the division LAB, University Medical Center Utrecht, The Netherlands. His research interests are in the field of cardiovascular biology, specifically focusing on innovation in biomarkers and drug targets, using data from Athero Express, the largest atherosclerotic plaque biobank worldwide, including
>4000 patients. Professor Pasterkamp coordinates national and EU-based consortia aiming to unravel biomarkers and determinants of plaque destabilisation, as well as mechanisms underlying atherosclerotic disease. He is a Board member of the Dutch Atherosclerosis Society, and a member of the editorial scientific boards of Arteriosclerosis, Thrombosis and Vascular Biology, Cardiovascular Research, Atherosclerosis, and the European Journal of Cardiovascular Pharmacology.

Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality worldwide. Vascular smooth muscle cells (VSMCs) play critical roles in the physiological and pathological vascular remodelling involved in atherogenesis, which may be either beneficial or detrimental for lesion pathogenesis. These functions are mediated by the ability of VSMCs to dynamically modulate their phenotype in response to local factors. The mechanisms controlling VSMC phenotypic plasticity have been extensively studied in vitro, leading to the development of a model explaining the shift between a differentiated, contractile phenotype and a phenotype characterized by the loss of VSMC marker gene expression, increase in extracellular matrix component synthesis, and increase in VSMC proliferation and migration upon exposure to various stimuli. However, in vivo understanding of the mechanisms controlling VSMC phenotypic switching is less comprehensive.

In the last decade, insights from lineage tracing studies have led to a re-evaluation of the contribution of VSMC phenotypic diversity to atherogenesis. Notably, it has been demonstrated that VSMCs undergo multiple phenotypic transitions, characterized by the expression of markers of alternative cell types, and congregate in atherosclerotic vessels. Genetic variants have been shown to substantially influence these transitions. With the advent of high-throughput transcriptomics and single-cell RNA sequencing, more detailed characterization of VSMC phenotypic diversity in vascular tissue is now possible. These technological advances offer new opportunities to understand the mechanisms underlying the plasticity of VSMC phenotypes, and the functional relevance of these transitions to vascular disease and remodelling. Ultimately such studies may help to identify targets that influence VSMC phenotypic switching.

Recent references

Aherrahrou R, Guo L, Nagraj VP, Aguhob AA, Hinkle J, Chen L, Soh JY, Lue D, Alencar GF, Boltjes A, van der Laan SW, Farber E, Fuller D, Anane-Wae R, Akingbesote ND, Manichaikul AW, Ma L, Kaikkonen MU, Björkegren JL, Onengut-Gumuscu S, Pasterkamp G, Miller CL, Owens GK, Finn AV, Navab M, Fogelman AM, Berliner JA, Civelek M. Genetic regulation of atherosclerosis-relevant phenotypes in human vascular smooth muscle cells. Circ Res 2020;doi: 10.1161/CIRCRESAHA.120.317415.

Depuydt MA, Prange KH, Slenders L, Örd T, Elbersen D, Boltjes A, de Jager SC, Asselbergs FW, de Borst GJ, Aavik E, Lönnberg T, Lutgens E, Glass CK, den Ruijter HM, Kaikkonen MU, Bot I, Slütter B, van der Laan SW, Yla-Herttuala S, Mokry M, Kuiper J, de Winther MP, Pasterkamp G. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ Res 2020;doi: 10.1161/CIRCRESAHA.120.316770.

Alencar GF, Owsiany KM, K S, Sukhavasi K, Mocci G, Nguyen A, Williams CM, Shamsuzzaman S, Mokry M, Henderson CA, Haskins R, Baylis RA, Finn AV, McNamara CA, Zunder ER, Venkata V, Pasterkamp G, Björkegren J, Bekiranov S, Owens GK. The stem cell pluripotency genes Klf4 and Oct4 regulate complex SMC phenotypic changes critical in late-stage atherosclerotic lesion pathogenesis. Circulation 2020; doi: 10.1161/CIRCULATIONAHA.120.046672.

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