Obesity is a major risk factor for cardiovascular diseases (CVD), the leading cause of global mortality. Endothelial dysfunction, a feature of obesity, has been identified as an early driver for CVD development. Low-grade, chronic inflammation due to obesity-induced subintimal lipid deposition plays an important role in the onset of obesity-associated CVD. Particularly macrophages accumulate in dysfunctional adipose tissue and vessels of obese patients and exert proinflammatory actions through e.g. release of cytokines.

Yet, the interplay between macrophages, adipocytes, and endothelial dysfunction in CVD development is not well understood. We recently identified ectopic olfactory receptor 2 (Olfr2) expression in vascular and adipose tissue macrophages (ATM), which was increased in obese mice. Of note, genetic deficiency for Olfr2 reduced atherosclerosis and macrophage inflammation.

The aim of this project is to uncover the role of Olfr2 in ATM-mediated inflammation in the context of obesity-induced endothelial dysfunction. We will address if Olfr2 affects adipose tissue inflammation and metabolism. Furthermore, we will assess vascular dysfunction in obese Olfr2-deficient and control mice by sonography and organ bath investigations.

Macrophages accumulate in perivascular adipose (PVAT) tissue in obesity and engage in a cross-talk with surrounding stromal and immune cells influencing vascular function. We hypothesize that the olfactory receptor 2 is an important mediator of PVAT-macrophage’s inflammatory response that mediates obesity-related endothelial dysfunction.

Clinical Relevance

Obesity greatly impacts overall health and can lead to the development of chronic diseases including CVD. Inflammation is a key mechanism rewiring adipose tissue, metabolic and vascular function. Yet, no clinical therapies targeting inflammation in obesity are available and novel pathways that curb adipose tissue inflammation while preserving host immunity are needed.

Approach

Preliminary data from our group confirms macrophage expansion in adipose tissue of obese mice. These macrophages upregulate surface Olfr2 expression (Figure 1).

Figure 1

Fig. 1: Flow cytometric analysis of adipose tissue from lean and obese mice. In obese mice, macrophages increase in number and upregulate Olfr2 expression.

In collaboration with Prof. Marco Orecchioni at Augusta University, we will address in this project:

Which PVAT-residing cell types express Olfr2 by histology and flow cytometry
Identify the impact of Olfr2 activation on metabolic alterations in obese wildtype and Olfr2-deficient mice
Assess the function of Olfr2 on macrophage activation and vascular function in the context of obesity by ultrasound and organ bath investigations
How Olfr2 affects the macrophage-adipocyte cross-talk

Affiliations - Holger Winkels

Affiliations - Martin Mollenhauer

Publication Record on PubMed - Holger Winkels

Publication Record on PubMed - Martin Mollenhauer

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024 (up to June)

Peters VBM, Matheis F, Erdmann I, Nemade HN, Muders D, Toubartz M, Torun M, Mehrkens D, Geissen S, Nettersheim FS, Picard F, Guthoff H, Hof A, Arkenberg P, Arand B, Klinke A, Rudolph V, Hansen HP, Bachurski D, Adam M,Hoyer FF, Winkels H, Baldus S, and Mollenhauer M (2024). Myeloperoxidase induces monocyte migration and activation after acute myocardial infarction. Front Immunol15, 1360700. doi:10.3389/fimmu.2024.1360700.
Roy P, Winkels H, Orecchioni M, Quesada-Masachs E, Riffelmacher T. Editorial: Role of innate and adaptive immune cells in the metabolic syndrome. Front Cell Dev Biol. 2024 Feb 22;12:1383642. doi: 10.3389/fcell.2024.1383642. PMID: 38455074; PMCID: PMC10917939.
Schelemei P, Wagner E, Picard FSR, and Winkels H (2024). Macrophage mediators and mechanisms in cardiovascular disease. FASEB J38, e23424. doi:10.1096/fj.202302001R.

2023

Freuchet A, Roy P, Armstrong SS, Oliaeimotlagh M, Kumar S, Orecchioni M, Ali AJ, Khan A, Makings J, Lyu Q, Winkels H, Wang E, Durant C, Ghosheh Y, Gulati R, Nettersheim F, and Ley K (2023). Identification of human exT(reg) cells as CD16(+)CD56(+) cytotoxic CD4(+) T cells. Nat Immunol 24, 1748-1761. doi:10.1038/s41590-023-01589-9.
Hof A, Guthoff H, Ahdab M, Landerer M, Schakel J, Niehues J, Schorscher M, Zimmermann O, Winkels H, von Stein P, Geissen S, Baldus S, Adam M, Mollenhauer M, and Mehrkens D (2023). Vascular Ultrasound for In Vivo Assessment of Arterial Pathologies in a Murine Model of Atherosclerosis and Aortic Aneurysm. Int J Mol Sci 24. doi:10.3390/ijms242015261.

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