MMP ‐2‐mediated Scube2 degradation promotes blood–brain barrier disruption by blocking the interaction between astrocytes and endothelial cells via inhibiting Sonic hedgehog pathway during early cerebral ischemia

In this issue, we demonstrate that MMP-2 could degrade astrocytic Scube2 and contribute to ischemic BBB disruption. The findings are as follows: (1) ischemia induces Scube2 degradation and MMP-2 has a direct interaction with Scube2 in astrocytes; (2) knockdown of Scube2 in astrocytes exacerbates BBB injury and downregulates Shh signaling pathway; (3) MMP-2 inhibition or overexpression of Scube2 in astrocytes protects endothelial cells from ischemic injury by activation of Shh signaling. We think these data provides a significant mechanistic understanding of the role of MMP-2 in stroke-induced loss of Scube2 and impaired Shh signaling leading to BBB dysfunction. BBB, blood –brain barrier; MMP-2, matrix metalloproteinase-2; Scube2, signal peptide-CUB-EGF domain-containing protein 2; Shh, Sonic hedgehog. AbstractWe have previously demonstrated a rapid secretion of matrix metalloproteinase-2 (MMP-2) in the ischemic brain. Since Scube2 can interact with Sonic hedgehog (Shh) to maintain blood –brain barrier (BBB) integrity via regulating the interaction between brain capillary endothelial cells (ECs) and perivascular astrocytes, and it is also a substrate of MMP-2, we hypothesized that the secreted MMP-2 could degrade Scube2 and contribute to ischemic BBB disruption. Using an in vitro ischemic model of 90-min oxygen–glucose deprivation/3-h reoxygenation (OGD/R) and an in vivo mouse stroke model of 90-min middle cerebral artery occlusion (MCAO) with 3-h reperfusion, we estab...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research