Impact of endothelial cells on the smooth muscle foam cell phenotype

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Endothelial cells (ECs) control many aspects of the phenotype of vascular smooth muscle cells (VSMCs) including their state of activation and tone. In the context of arteriosclerosis, EC dysfunction is discussed to precede plaque formation that includes transdifferentiation of VSMCs to macrophage-like foam cells. While several regulatory determinants involved in this phenotypic switch were already described, it is unknown whether altered paracrine communication between ECs and VSMCs contributes to this process. For the study of those cellular interactions, we developed a spheroid-based 3D cell culture model that allows for the generation of size-defined vascular organoids composed of a single sheet of ECs covering a core of VSMCs. After separating both cell types, transcriptome and proteome analyses revealed that ECs stabilize the differentiation of VSMCs and decrease their expression of foam cell markers as well as of genes associated with different aspects of lipid handling and metabolism. The control of the VSMC gene expression pattern thereby appeared at least in part dependent on prostanoid-mediated signaling (especially prostacyclin). We further investigated whether the gene expression associated with the prostanoid system is altered in a pro-arteriosclerotic environment that stimulates both EC dysfunction and VSMC foam cell formation. To this end, we performed metaanalyses of scRNAseq databases, which revealed that especially endothelial Ptgs1 (cyclooxygenase 1) and Ptgis (prostacyclin synthase) expression (enzymes rate limiting for prostacyclin generation) is downregulated in ApoE-deficient mice fed a high fat diet. Similarly, hypertension and familial hypercholesterinemia appeared to decrease the expression of genes associated with ‘prostaglandin secretion’ in ECs from a human coronary artery. Considering these data, we hypothesize that dysfunction of ECs as evoked by chronic exposure to pro-arteriosclerotic stressors such as high glucose (diabetes type II) or lipid (dyslipidemia) serum concentrations limits the efficacy of ECs to maintain the differentiation of VSMCs thereby facilitating a phenotypic shift favoring the development of VSMC foam cells. Based on a 3D human organoid cell culture model, this study will investigate i) the impact of high glucose and oxLDL levels on the capacity of ECs to maintain the VSMC phenotype, ii) the general influence of clinically relevant pharmacological inhibitors of prostanoid generation on the VSMC phenotype switch in a pro-arteriosclerotic environment and iii) the role of prostacyclin-dependent signaling in this context.