Vascular adventitial cells and vascular remodeling: when a harp of thousand strings does not keep in tune so long

The tunica adventitia of blood vessels is a highly heterogeneous microenvironment comprising diverse cell types. Beyond providing structural scaffolding, adventitial fibroblasts act as dynamic, responsive cells that contribute to vascular homeostasis mainly through regulation of collagen, fibronectin and elastin expression and paracrine effects that promote vascular inflammation. Their dysregulation leads to the onset and progression of several diseases. Signaling pathways in adventitial fibroblasts, particularly DDR2, hypoxia-ERK1/2 MAPK and PI3K/Akt signaling, impact cell proliferation, pro-fibrotic gene expression and cellular response to stress. Furthermore, non-coding RNAs and novel epigenetic mechanisms significantly impact adventitial fibroblast function. Adventitial fibroblasts promote sex-related variations in the prevalence and severity of vascular diseases. Rapid advances in single-cell transcriptomics, biomarker development and other molecular and imaging techniques promise deeper insights into adventitial fibroblast biology, unravelling their heterogeneity and functional variability, and their role in extracellular matrix remodeling and paracrine signaling. These in turn would pave the way for innovative strategies to target pro-fibrotic fibroblast subpopulations and prevent adverse vascular remodeling. This review provides an overview of adventitial fibroblast function and the role of these cells in atherosclerosis, hypertension, diabetes, aneurysm and age-related vascular dysfunction, underscoring the need for a paradigm shift in vascular biology, positioning the adventitia as a critical regulator of vascular health and disease.