Rethinking vascular repair: Endothelial ageing, progenitor cell dysfunction, and senotherapeutic rescue

Vascular ageing is increasingly recognised as a key driver of cardiovascular and cerebrovascular disease rather than merely a passive consequence of chronological time. Progressive loss of endothelial regenerative capacity remains central to this process and is characterised by endothelial progenitor cell dysfunction, accumulation of senescent endothelial cells, and aberrant changes in the endothelial secretome. Taken together these alterations contribute to ineffective endothelial repair, chronic (low-grade) vascular inflammation and impaired endothelial barrier integrity and function, ultimately leading to vascular dysfunction. Over the past two decades, accumulating evidence from our group and others has provided mechanistic insight into how oxidative stress, redox imbalance, mitochondrial dysfunction and cellular senescence collectively impair endothelial (barrier) function and compromise overall vascular homeostasis. Age-dependent changes in progenitor cell number and function further limit the capacity of vasculature to respond to damage and stress. More recent work demonstrate that senolytics and senomorphics can preserve endothelial function and delay age-related vascular and cerebral barrier dysfunction in experimental models. This mini review supports an emerging framework that positions defective endothelial renewal as a critical driver of vascular ageing and endothelial dysfunction. We propose that concomitant application of senotherapeutics with progenitor cell-based or secretome-based approaches represents a critical next step in precision vascular medicine.