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An interplay of microglia and matrix metalloproteinase MMP9 under hypoxic stress regulates the opticin expression in retina.

ABSTRACT: Inflammation plays a key role in the pathogenesis of retinal vascular diseases. We have shown earlier an increase in the activity of matrix metalloproteinases in the vitreous and tears of preterm born babies with retinopathy of prematurity (ROP) compared to those with no-ROP leading to a shift in the balance of angiogenic (vascular endothelial growth factor [VEGF], matrix metalloproteinase [MMPs], complement component [C3]) and anti-angiogenic (opticin, thrombospondin) in ROP eyes. We now confirmed that tear MMP levels in premature infants perfectly correlates with disease severity. Next, we demonstrated that a reduced opticin levels in ROP vitreous are regulated by MMPs secreted by activated microglia. Upon exposing the human microglia cell line (CHME3) to hypoxia, an increased expression of inflammatory proteins (MMP9, VEGF) was noticed while opticin reduced significantly (p = 0.005). Further, the reduced opticin's expression by microglial cells under hypoxia could be rescued by inhibiting the MMP activity using doxycycline and EDTA. The inhibition of MMP activity altered the expression of other key signaling molecules under hypoxia. Our study clearly explains that increased activity of MMPs under hypoxia regulates the expression of opticin as seen in the vitreous humor of ROP and could serve as a potential target for ROP management.

SUBMITTER: Patnaik S

PROVIDER: S-EPMC8018966 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CCL5 of glioma-associated microglia/macrophages regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase 2.

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Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke.

Project description:We assessed the association of genetic variation in MMP3 and MMP9 with risk of myocardial infarction and stroke.A case-control study was conducted among members of Group Health (GH), a large-integrated health care delivery system. Case subjects with incident non-fatal myocardial infarction (n=854), ischemic stroke (n=367), and hemorrhagic stroke (n=66) were identified and validated. A matched control group was selected from among GH members without myocardial infarction or stroke (n=2696). Haplotype-tagging sets of single-nucleotide polymorphisms (SNPs) in MMP3 and MMP9 were genotyped.MMP3 haplotype 2 was associated with reduced risk of myocardial infarction (adjusted odds ratio (OR) per copy=0.80, 95% confidence interval 0.66, 0.98) and increased risk of hemorrhagic stroke (OR=1.69, 95% confidence interval 1.05, 2.75). Results for MMP3 haplotype 2 and ischemic stroke resembled those for myocardial infarction but did not achieve statistical significance (OR=0.85, 95% confidence interval 0.64, 1.12). No individual SNP identified MMP3 haplotype 2, and none of the individual MMP3 SNPs were associated with myocardial infarction or stroke. MMP9 haplotypes or SNPs were not associated with myocardial infarction or stroke.MMP3 haplotype may predict both cardiac events and stroke.

| S-EPMC3077423 | biostudies-literature

Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration.

Project description:We investigated the hypothesis that endothelial cells activated by erythropoietin (EPO) promote the migration of neuroblasts. This hypothesis is based on observations in vivo that treatment of focal cerebral ischemia with EPO enhances the migration of neuroblasts to the ischemic boundary, a site containing activated endothelial cells and angiogenic microvasculature. To model the microenvironment within the ischemic boundary zone, we used a coculture system of mouse brain endothelial cells (MBECs) and neural progenitor cells derived from the subventricular zone of the adult mouse. Treatment of MBECs with recombinant human EPO (rhEPO) significantly increased secretion of matrix metalloproteinase 2 (MMP2) and MMP9. rhEPO-treated MBEC supernatant as conditioned medium significantly increased the migration of neural progenitor cells. Application of an MMP inhibitor abolished the supernatant-enhanced migration. Incubation of neurospheres alone with rhEPO failed to increase progenitor cell migration. rhEPO activated phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase (ERK1/2) in MBECs. Selective inhibition of the PI3K/Akt and ERK1/2 pathways significantly attenuated the rhEPO-induced MMP2 and MMP9, which suppressed neural progenitor cell migration promoted by the rhEPO-activated MBECs. Collectively, our data show that rhEPO-activated endothelial cells enhance neural progenitor cell migration by secreting MMP2 and MMP9 via the PI3K/Akt and ERK1/2 signaling pathways. These data demonstrate that activated endothelial cells can promote neural progenitor cell migration, and provide insight into the molecular mechanisms underlying the attraction of newly generated neurons to injured areas in brain.

| S-EPMC6675216 | biostudies-literature

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