Matrix metalloproteinase‑9 in hemorrhagic transformation after acute ischemic stroke (Review)

Abstract

Hemorrhagic transformation (HT) is a devasting complication following acute ischemic stroke with high morbidity and mortality. The pathogenesis of HT mainly involves ischemia‑reperfusion‑induced oxidative stress, neuroinflammation, thrombolytic therapy‑associated toxicity and, most critically, blood‑brain barrier (BBB) disruption. Matrix metalloproteinase‑9 (MMP‑9) serves as a critical mediator of HT through degrading extracellular matrix components and disrupting tight junction proteins, thereby compromising BBB integrity. Thus, elaborating the underlying molecular mechanisms of MMP‑9 in destroying BBB and promoting HT is essential to improve the outcome of ischemic stroke patients. Furthermore, to provide beneficial insights for the treatment of ischemic stroke, precise understanding of the potential role of MMP‑9 as a biomarker and treatment target to predict and ameliorate the risk of HT is also necessary.

Keywords: biomarker; hemorrhagic transformation; ischemic stroke; matrix metalloproteinase‑9; treatment.

Figure 1.

Domain structures of MMP-9. MMP-9 contains several domains, including a signal peptide domain, a prodomain, a catalytic domain with a Zn²⁺ binding site, a fibronectin domain and a hemopexin-like domain. The figure was generated with Biorender (https://www.biorender.com). MMP-9, matrix metalloproteinase-9.

Figure 2.

Schematic representation of the dynamic changes in MMP-9 following ischemic stroke. Within 7 days from onset, MMP-9 expression/activity increases rapidly and peaks within 24 h, which exacerbates BBB disruption, edema and neuroinflammation, thereby promoting HT. At 7–14 days after ischemic stroke, MMP-9 expression/activity remains at a high level, facilitating tissue repair and angiogenesis through degrading damaged ECM. From weeks to months after ischemic stroke, MMP-9 expression/activity decreases gradually, promoting ECM remodeling and functional recovery. The figure was generated with Biorender (https://www.biorender.com). MMP-9, matrix metalloproteinase-9; BBB, blood-brain barrier; HT, hemorrhagic transformation; ECM, extracellular matrix.

Figure 3.

The biological structure of blood-brain barrier. The components of BBB mainly include endothelial cells with tight junctions, astrocytes, pericytes and ECM. Claudin, occludin and ZO-1 are common TJPs secreted by endothelial cells. ECM of the brain consists of neuro-ECM, BM and luminal ECM. Astrocytes and pericytes are embedded in the BM. All these different cells and structures are involved in maintaining the integrity and function of BBB. The figure was generated with Biorender (https://www.biorender.com). BBB, blood-brain barrier; BM, basement membrane; ECM, extracellular matrix; CNS, central nervous system.

Figure 4.

Involvement of MMP-9 in HT after ischemic stroke. HT following ischemic stroke is primarily driven by BBB dysfunction, which involves three interconnected pathological processes including oxidative stress, neuroinflammation and thrombolytic therapy-associated toxicity. These mechanisms collectively disrupt BBB integrity through direct structural injury and indirect MMP-9-dependent pathways. The figure was generated with Biorender (https://www.biorender.com). MMP-9, matrix metalloproteinase-9; HT, hemorrhagic transformation; PDGF, platelet-derived growth factor; AnxA2, annexin A2; MAPK, mitogen-activated protein kinase; LRP, low-density lipoprotein receptor-related protein; BBB, blood-brain barrier; DAMPs, damage-associated molecular patterns; ROS, reactive oxygen species; RNS, reactive nitrogen species; HMGB1, high-mobility group box1; TLR4, toll-like receptor 4; PI3K, phosphatidylinositol-3 kinase; Akt, protein kinase B; NF-κB, nuclear factor-κB; AP-1, activator protein-1; ECM, extracellular matrix; TJP, tight junction protein; TEER, trans-endothelial electrical resistance.