Sonic hedgehog-matrix metalloproteinase crosstalk in neurovascular ageing and stroke: a potential mechanistic link

Abstract Neurovascular ageing is a major contributor to cerebrovascular vulnerability and poor stroke outcomes in older adults. Progressive deterioration of the neurovascular unit (NVU), driven by oxidative stress, neurovascular coupling dysfunction, blood–brain barrier (BBB) disruption, inflammageing, cellular senescence, mitochondrial dysfunction, and impaired autophagy compromises neurovascular resilience and increases susceptibility to ischemic injury. Among the molecular pathways implicated in these processes, Sonic hedgehog (Shh) signaling and matrix metalloproteinases (MMPs) are important regulators of neurovascular remodeling, BBB integrity, and post-stroke recovery. Although these pathways have largely been investigated independently, emerging evidence suggests potential bidirectional interactions between Shh signaling and MMP activity. In particular, Shh/Gli1 signaling has been associated with regulation of MMP-2 and MMP-9 in experimental models, whereas MMP-2 can disrupt SCUBE2, an extracellular regulator of Shh ligand presentation, providing a potential mechanism for reciprocal pathway modulation. This review examines the Shh-MMP axis as a potential mechanistic link between neurovascular ageing and ischemic vulnerability, integrating current evidence to evaluate how dysregulation of these pathways may contribute to BBB dysfunction, extracellular matrix remodeling, neuroinflammation, and impaired neurovascular repair. We further discuss the potential therapeutic implications of modulating the Shh-MMP axis to preserve neurovascular resilience and improve cerebrovascular outcomes in the ageing brain, while highlighting the importance of temporal and cell-specific targeting. Graphical Abstract Ageing-associated oxidative stress, inflammageing, and cellular senescence disrupt the balance between protective Shh signaling and degradative MMP activity within the NVU. Suppression of Shh signaling together with persistent MMP-2/9 activation promotes BBB dysfunction, ECM remodeling, neurovascular uncoupling, and impaired cerebral perfusion, thereby increasing susceptibility to IS and limiting recovery. The Shh-MMP axis therefore represents a potential mechanistic link between neurovascular ageing and stroke and may serve as a promising therapeutic target for restoring neurovascular resilience and improving cerebrovascular outcomes in the ageing population. (NVU: Neurovascular unit; BBB: Blood-brain barrier; MMP: Matrix metalloproteinases; Shh: Sonic hedgehog; ECM: Extracellular matrix; IS: Ischemic stroke)