Research Program

This project investigates how microvascular endothelial cell (MVEC) heterogeneity and plasticity regulate adipose tissue homeostasis. Using single-cell omics in human and murine models, we explore how high-fat diets (HFD) alter endothelial identity and function. Our preliminary data highlight the role of caveolin-1 (Cav1) and endothelial nitric oxide synthase (eNOS) in lipid handling and CD36 nitrosation. We will dissect NO signaling in MVECs using EC-specific Cav1 and eNOS KO/KI mice. Spatial transcriptomics and metabolic profiling will reveal how dysfunctional eNOS/Cav1 signaling impacts fat accumulation and cardiovascular hemodynamics. In vitro co-culture and organoid models will assess how redox modifications of CD36 affect lipid uptake. Finally, CD36 knock-in mice will validate key pathways in vivo. This work may uncover novel endothelial targets for obesity-related disorders.

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Endothelial cells form the inner lining of all blood vessels in the human body. The endothelial cells of blood capillaries (the most abundant and smallest blood vessels of the body) face (i) the blood stream with their lumenal (or apical) cell surface and (ii) the cells of a given organ with their ablumenal (or basolateral) cell surface. They therefore form the cellular link between the blood and organ. Notably, endothelial cells can react to alterations in the blood by releasing multiple different angiocrine signals to the cells of a given organ. The alterations in the blood could be mechanical (due to changes in blood flow, blood pressure or blood viscosity) or chemical (due to alterations in nutrients, gases or hormones). Notably, an increased blood flow can result in mechanical stretching of endothelial cells, so that they secrete angiocrine signals to induce organ growth and regeneration. In a collaborative effort of the Hirschi and Lammert laboratories, the ability of capillary endothelial cells to release organ growth-promoting angiocrine signals will be investigated by using “omics” technology and bioinformatics. The identified angiocrine signals from the endothelial cells and corresponding receptors on cells of a given organ can be used to develop therapeutics to booster organ regeneration.    

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Continuous changes in vascular structure and function play a key role in the vascular disease development. The transition from healthy to diseased vessels depends on exogenous and endogenous factors affecting the plasticity of endothelial cells (ECs) and vascular smooth muscle cells. This process is characterized by low-grade inflammation, reduced nitric oxide (NO) availability, mitochondrial dysfunction, and extracellular matrix remodeling. High sodium intake impairs vascular function and is linked to increased cardiovascular risk. Thus, high salt intake promotes a pro-inflammatory immune response, impairs mitochondrial function and NO availability. It also stiffens ECs and enhances myogenic tone in resistance arteries, suggesting a direct impact on EC phenotype and plasticity. Recently, we found evidence that high salt may also induce cellular “salt memory,” altering vascular plasticity and increasing susceptibility to vascular damage following a second hypertensive insult. The exact mechanisms underlying this effect remain unclear and will be explored through a multimodal approach using in vitro cell systems, ex vivo vascular function analyses, and in vivo animal models.

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Aging is an independent risk factor for cardiovascular diseases. Characteristics are increased oxidative stress and chronic inflammation leading to endothelial cell (EC) senescence and a phenotypic switch in vascular smooth muscle cells (SMC). Both phenomena, which affect only a fraction of cells, contribute to age-associated vascular dysfunction resulting in e.g. hypertension. However, the mechanisms underlying the induction of the different phenotypes are not known. Therefore, the aim of project 4 is to investigate whether endothelial cell senescence precedes the smooth muscle cell transitions in different vascular beds. To achieve this aim, single cell RNAseq of murine tissue sections as well as human EC and SMC will be performed followed by bioinformatic analyses. After identification of potential pleiotropic regulators, proof of causality will be performed by lentiviral overexpression or downregulation in cells.

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After injury, resident fibroblasts differentiate into myofibroblasts in response to mechanical cues or cytokines like transforming growth factor β1 (TGF-β1), but also to certain lipids. This differentiation is required during the healing phase. However, persistent activation of this cell type leads to adverse remodeling and fibrosis. Tissue-resident fibroblasts are heterogeneous with organ-specific subtypes and a “core” subtype present in all tissues. However, it is not clear, which subtype goes through the differentiation process. Therefore, the aim of project 6 is to investigate whether myofibroblast differentiation follows organ-specific pathways that are modulated by extrinsic and intrinsic conditions. To achieve this aim, single cell RNAseq of fibroblasts from different organs differentiated ex vivo will be performed followed by bioinformatic analyses. For proof of causality identified regulators will be overexpressed or downregulated in fibroblasts for validation.

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This project investigates how the stiffness of the cardiac cellular substrate influences the interaction between cardiomyocytes (CMs) and fibroblasts (FBs), as well as the release of proinflammatory cytokines. The collaboration with UVA combines innovative biomaterials with biomechanical single-cell analyses. CMs dynamically adjust their passive stiffness after myocardial infarction, a process involving cytokines such as IL-6 and TGF-β. By culturing rat CMs and FBs on synthetic substrates with defined stiffness, the project aims to examine mechanosensitive signaling pathways and their effects on cell morphology, cytokine release, and CM function. In addition, substrate-dependent changes in DNA methylation will be assessed using Nanopore sequencing, and cell type-specific transcriptional changes will be analyzed through bulk RNA sequencing. The aim is to gain a better understanding of early mechanical and molecular remodeling processes in the non-ischemic myocardium.

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The group of Gödecke showed that a short term Insulin-like growth factor I (Igf1) application after acute myocardial infarction (MI) reduces scar size, and improves angiogenesis and pump function by phenotypic modulation neutrophils and macrophages towards an attenuated pro-inflammatory phenotype in vivo. Single cell sequencing revealed an abundant endogenous expression of Igf1 in cardiac fibroblasts and pericardial WT1+ expressing mesenchymal cells. The group of Matthew Wolf, by using an advanced lineage tracing system revealed that cardiac myocytes (CM) can reenter the cell cycle post-MI and eventually can from new CM. RNA sequencing of cycling CM revealed a transcription signature similar to that of epicardial or pericardial WT1⁺ progenitor cells and a striking upregulation of Igf1 expression. In a collaborative project, both groups plan to assess the effect of endogenous Igf1 on the modulation of cardiac cellular phenotypes and functional adaptation post MI. To this end, functional analysis, cell-type specific knockout mice, lineage tracing, single-cell sequencing and bioinformatics will be employed.

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