MMP-9: A New Player in Cerebral Vasospasm Pathophysiology

Ananth Vellimana1, Byung Han, PhD1, Eric Milner, BS1, Mengliang Zhou, MD, PhD1


Keywords: aneurysm, subarachnoid hemorrhage, vasospasm, blood, risk factor

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     Matrix metalloproteinase 9 (MMP-9) is strongly implicated in the pathophysiology of ischemic stroke, but its role in SAH is poorly understood. Past studies show that MMP-9 is upregulated after experimental SAH, MMP-9 contributes to early brain injury after experimental SAH, and MMP-9 activity correlates with vasospasm severity in human SAH.
     We directly examined whether MMP-9 exacerbates SAH-induced vasospasm and neurological deficits, and we explored potential mechanisms by which MMP-9 causes its deleterious effects.
     10-12 weeks old male MMP-9 knockout (KO) mice and wild-type (WT) controls were subjected to sham surgery or endovascular perforation SAH. Separately, 10-12 week old male WT mice were treated with vehicle or the MMP-9 inhibitor minocycline (45 mg/kg) beginning 2h before sham or SAH surgery. Vasospasm was assessed on post-SAH day 3; neurological function was assessed daily. Endothelial nitric oxide synthase (eNOS) expression was assessed by western blot and immunohistochemistry. In vivo vascular reactivity was assessed via closed cranial window.
     Genetic and pharmacologic inhibition of MMP-9 led to strong protection against vasospasm and neurological deficits following SAH. Also, eNOS expression and NO-mediated vasodilation were greater in MMP-9 KO mice compared to WT mice; and administration of the NOS inhibitor L-NAME to MMP-9 KO mice prevented the previously observed protection against SAH-induced neurovascular deficits.
     This is a retrospective study.
     Our data indicate that MMP-9 plays a causal role in vasospasm pathogenesis.
     It also suggests that MMP-9-mediated inhibition of eNOS is responsible for this deleterious effect, and that minocycline is a promising new therapeutic strategy for SAH patients.


Project Roles:

A. Vellimana (), B. Han (), E. Milner (), M. Zhou ()