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Modulation of endothelial cell morphogenesis in vitro by MMP-9 during glial-endothelial cell interactions

N Chandrasekar1, S Jasti, W K Alfred-Yung

  • 1Department of Biomedical and Therapeutic Sciences, UIC College of Medicine at Peoria, Illinois 61656, USA.

Clinical & Experimental Metastasis
|July 13, 2001
PubMed

Insights

Matrix metalloproteinase-9 (MMP-9) is crucial for capillary formation in brain endothelial cells cocultured with glioblastoma. Its activity, regulated by protein kinase C (PKC), drives endothelial cell morphogenesis and network development.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Glioblastoma cells interact with brain microvascular endothelial cells.
  • Matrix metalloproteinases (MMPs) play roles in cell signaling and tissue remodeling.
  • Endothelial cell function is critical for brain vascularization.

Purpose of the Study:

  • To investigate the roles of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in capillary formation.
  • To elucidate the signaling pathways involved in MMP-9-mediated endothelial cell morphogenesis in glioblastoma cocultures.

Main Methods:

  • Coculture of human brain microvascular endothelial cells with SNB19 glioblastoma cells.
  • Stimulation with phorbol 12-myristate 13-acetate (PMA) to activate protein kinase C (PKC).
  • Assay of MMP-9 activity, capillary network formation, and inhibition using specific antibodies, inhibitors (Batimastat, calphostin-C, PD98059), and cytoskeletal inhibitors (cytochalasin-D, colchicine-B).

Main Results:

  • PMA stimulation induced MMP-9 production and capillary network formation in cocultures.
  • Recombinant MMP-9 enhanced capillary formation, while anti-MMP-9 antibodies and TIMP-1 inhibited it.
  • PKC activation, MEKK signaling, and actin cytoskeleton dynamics were essential for PMA-induced MMP-9 expression and capillary formation.

Conclusions:

  • MMP-9 is a key mediator of endothelial cell capillary formation in glial/endothelial cocultures.
  • PKC signaling pathway is involved in regulating MMP-9 expression and subsequent angiogenesis.
  • MMP-9 activity is critical for endothelial cell morphogenesis and the development of functional capillary networks in the brain microenvironment.

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