The crosstalk between adventitial ACKR3+ fibroblasts and plaque-associated microvasculature in the pathogenesis of atherosclerosis

• Applicant: Dr. Laura Parma
• Subject Area: Cardiac and Vascular Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547456039

Adventitial fibroblasts play a pivotal role in the remodeling of the adventitia during the progression of atherosclerosis, influencing vasa vasorum expansion and the formation of intraplaque neovessels. In preliminary experiments utilizing human and murine scRNAseq datasets and reporter Ackr3eGFP mice, we have identified adventitial fibroblasts in atherosclerotic blood vessels as the primary cells expressing the Atypical Chemokine Receptor 3, ACKR3. Moreover, we also discovered that inhibition of ACKR3 leads to a significant reduction of ex-vivo angiogenesis. Interestingly, genome-wide association studies have established the link between cardiovascular disease and the expression of CXCL12, ACKR3´s ligand. The activation of the CXCR4 receptor by CXCL12 is known for its role in promoting the recruitment of leukocytes to atherosclerotic lesions and altering the permeability of arterial endothelial cells. However, the effects of its interaction with ACKR3, which does not induce cell migration but instead regulates the bioavailability of CXCL12, remain unclear. Therefore, based on our preliminary findings, we now aim at investigating the role of AKCR3+ fibroblasts in the remodeling of adventitia during atherosclerosis using various murine models. First, we will map the spatiotemporal distribution of Ackr3eGFP fibroblasts, along with other cell types, in the adventitia of atherosclerotic lesions with and without intraplaque neovessels. Next, we will use PdgfrαCreERT2+Ackr3fl/flApoe-/- mice to study the consequences of fibroblasts specific knockout of ACKR3 on the composition of diseased adventitia in a chronic, age-induced model for atherosclerosis, and on neovessel formation originating from adventitial vasa vasorum using a vein-graft mouse model to obtain advanced, human-like atherosclerotic plaques. Finally, our investigation will also focus on the identification of the intracellular signaling pathways that mediate the function of ACKR3+ fibroblasts during atherosclerotic adventitial remodeling, by using single cell RNA sequencing and in vitro and ex vivo assays. This comprehensive investigation will shed light on the role of ACKR3+ adventitial fibroblasts in the context of advanced atherosclerosis and the findings from this project may pave the way for novel strategies to mitigate the impact of adventitia remodeling in the context of atherosclerotic diseases.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Johan Duchene, Ph.D.