The Aging Extracellular Matrix as a Driver of Vascular Reprogramming

Cardiovascular aging is accompanied by profound remodeling of the extracellular matrix (ECM). Growing evidence suggests that ECM not only acts as a structural scaffold but also actively regulates cell behavior and vascular homeostasis. During aging, the vascular ECM undergoes numerous molecular, architectural, and biochemical changes, including collagen accumulation, elastin fragmentation, pathological crosslinking, matrikines production, and progressive matrix stiffening. These changes reshape the vessel wall’s biochemical and mechanical landscape, reflecting how cells respond to their microenvironment. Vascular cells continuously interpret matrix-derived cues through integrins, discoidin, syndecans, ion channels, and downstream pathways such as FAK, RhoA/ROCK, and YAP/TAZ. As the ECM ages, continuous activation of these pathways promotes endothelial dysfunction, modulation of the vascular smooth muscle cell phenotype, fibroblast activation, inflammation, calcification, and induction of senescence. Consequently, the aging ECM emerges as an instructive niche that can determine and reprogram vascular cell identity and function. Interestingly, the relationship between ECM remodeling and senescent state is bidirectional. Senescent vascular cells profoundly affect matrix composition by producing a plethora of factors involved in ECM production and remodeling, while age-associated ECM alterations, including collagen deposition, increased stiffness, and active matrikines, can induce or reinforce senescence-associated phenotypes. This bidirectional interaction establishes a self-amplifying loop that accelerates vascular dysfunction and cardiovascular aging. In this work, we discuss the molecular and structural hallmarks of ECM aging, the mechanisms by which vascular cells sense and interpret matrix-derived signals, and emerging evidence linking ECM remodeling to senescence and vascular remodeling. In addition, we highlight unanswered questions and opportunities aimed at preserving ECM integrity, modulating mechanotransduction, and restoring a more youthful extracellular environment. In sum, this review supports the notion that aging ECM is not a passive bystander, but a pivotal driver and a promising intervention target for promoting vascular aging and cardiovascular diseases.