Blood-brain barrier permeability is regulated by matrix metalloproteinase-3 via the ERK signaling pathway

Background The blood–brain barrier (BBB) regulates the exchange of molecules between the brain and peripheral blood and is composed primarily of microvascular endothelial cells (BMVECs), which form the lining of cerebral blood vessels and are linked via tight junctions (TJs). The BBB is regulated by components of the extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the basal lamina of the ECM, which forms part of the BBB. Thus, we investigated whether MMP3 modulates BBB permeability. Methods Experiments included in-vivo assessments of isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and MMP3-deficient (MMP3-KO) mice, as well as in-vitro assessments of the integrity of monolayers of WT and MMP3-KO BMVECs (via measurements of transendothelial electrical resistance [TEER] and transwell assays in a co-culture of BMVECs with astrocytes and the expression of junction proteins. Results Compared to assessments in WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT mice that had been treated with MMP3 (WT + MMP3), while anesthesia emergence times were shorter in MMP3-KO mice and longer in WT + MMP3 mice than in WT mice. Extravasation of systemically administered dyes was also lower in MMP3-KO mouse brains, and higher in WT + MMP3 mouse brains, than in the brains of WT mice, and the results from both TEER and transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced, barrier integrity in either BMVEC monolayers or the co-culture. MMP3 deficiency also increased the abundance of TJ and VE-cadherin proteins in BMVECs, and the protein abundance declined when MMP3 activity was upregulated in BMVECs, but not when the cells were treated with an inhibitor of extracellular signal related kinase (ERK). Conclusion MMP3 increases BBB permeability by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins abundance in BMVECs. Collectively, these observations suggest that MMP3 could be therapeutically targeted to manipulate BBB permeability and treat neurological disease.