Increase in Blood‐Brain Barrier (BBB) Permeability Is Regulated by MMP3 via the ERK Signaling Pathway

Abstract

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 ECM’s basal lamina, which forms part of the BBB. Oxidative stress is implicated in activation of MMPs and impaired 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 and the expression of junction proteins. Results. Compared to WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT 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. 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. The results from both TEER and Transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced barrier integrity in either BMVEC or the coculture. MMP3 deficiency also increased the abundance of TJs 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 following the administration of isoflurane by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins in BMVECs.

Regulation of vascular permeability in cancer metastasis

“…This tripeptide promotes VE‐cadherin phosphorylation to enhance vascular permeability in a CXC chemokine receptor 2 (CXCR2) signaling system–dependent manner. ADAM10, 17, and MMP3 degrade junction proteins 12‐14 . Angiomodulin produced in human bladder carcinoma cells and fibroblasts binds integrin ανβ3 to induce actin stress fibers, resulting in loosening of the VE‐cadherin–mediated intercellular junctions 15 .…”

“…These enzymes are produced as proenzymes and later processed by other proteases to make active forms. Active enzymes can degrade junction proteins to reduce cell‐cell contact and increase vascular permeability 12‐14 Permeability factors downregulate expression of genes encoding junction proteins (Figure 1A‐3).…”

“…ADAM10, 17, and MMP3 degrade junction proteins. 12 , 13 , 14 Angiomodulin produced in human bladder carcinoma cells and fibroblasts binds integrin ανβ3 to induce actin stress fibers, resulting in loosening of the VE‐cadherin–mediated intercellular junctions. 15 Epithelial tumor cells produce high levels of angptl4, which binds integrin α5β1, claudin‐5, and VE‐cadherin to disrupt endothelial cell‐cell interactions.…”

“…Active enzymes can degrade junction proteins to reduce cell‐cell contact and increase vascular permeability. 12 , 13 , 14 Permeability factors downregulate expression of genes encoding junction proteins (Figure 1 A‐3). Many permeability factors intervene in the gene regulatory system of endothelial cells to downregulate junction proteins.…”

LncRSPH9-4 Facilitates Meningitic Escherichia coli-Caused Blood–Brain Barrier Disruption via miR-17-5p/MMP3 Axis

“…MMP3 is a member of the MMP family, which is widely involved in the breakdown of extracellular matrix proteins during tissue remodeling, such as embryonic development and reproduction, as well as in disease processes, such as arthritis and tumor metastasis [47]. MMP3 can degrade collagen, elastin, fibronectin, laminin, as well as tight junctions, so as to increase vascular permeability and disrupt the BBB [25,41,48,49]. In hBMECs, our results suggested that lncRSPH9-4 was able to regulate MMP3 expression by acting as a competitive sponge of miR-17-5p.…”