Hypoxia of endothelial cells leads to MMP-2-dependent survival and death.

Abstract

Exposure of endothelial cells (ECs) to hypoxia has separately been shown to induce their angiogenesis or death. Matrix metalloproteinase (MMP)-2 is associated with EC angiogenesis, although recent studies also implicate this molecule in EC death. We studied the effect of hypoxia in the absence or presence of TNF-alpha (characteristic of the inflammatory microenvironment accompanying hypoxia) on MMP-2 expression and its role in angiogenesis (proliferation, migration, and tube formation) and in the death of primary human umbilical vein endothelial cells (HUVECs). Hypoxia alone (24-48 h in 0.3% O(2) in the hypoxic chamber) and furthermore, when combined with TNF-alpha, significantly enhanced MMP-2 expression and activity. Hypoxia also led to a reduction in membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 mRNA and protein while enhancing the expression of alpha(v)beta(3) integrin and the cytoskeletal protein phosphopaxillin. Moreover, hypoxia led to colocalization of alpha(v)beta(3) and MMP-2, but not MT1-MMP, with phosphopaxillin in ECs. These results suggest MT1-MMP-independent activation of MMP-2 during hypoxia and support interactions between the ECM, integrins, and the cytoskeleton in hypoxia-induced MMP-2-related functions. Hypoxia enhanced EC migration in an MMP-2-dependent manner while leading to a reduction of cell number via their apoptosis, which was also dependent on MMP-2. In addition, hypoxia caused an aberrant tubelike formation on Matrigel that appeared to be unaffected by MMP-2. The hypoxia-induced, MMP-2-dependent migration of ECs is in accordance with the proangiogenic role ascribed to MMP-2, while the involvement of this protease in the hypoxia-related death of ECs supports an additional apoptotic role for this protease. Hence, in the hypoxic microenvironment, MMP-2 appears to have a dual autocrine role in determining the fate of ECs.

• Authors: Yaara Ben-Yosef, Ariel Miller, Sarah Shapiro, Nitza Lahat
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 289 Issue 5 Pg. C1321-31 (Nov 2005) ISSN: 0363-6143 [Print] United States
• PMID: 16210427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytoskeletal Proteins
• Integrin alphaVbeta3
• PXN protein, human
• Paxillin
• Phosphoproteins
• Tumor Necrosis Factor-alpha
• Tissue Inhibitor of Metalloproteinase-2
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 2
• Oxygen

Topics

• Cell Death (physiology)
• Cells, Cultured
• Cytoskeletal Proteins (physiology)
• Endothelial Cells (physiology)
• Gene Expression Regulation (physiology)
• Humans
• Integrin alphaVbeta3 (physiology)
• Matrix Metalloproteinase 2 (biosynthesis)
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (physiology)
• Oxygen (physiology)
• Paxillin
• Phosphoproteins (physiology)
• Time Factors
• Tissue Inhibitor of Metalloproteinase-2 (physiology)
• Tumor Necrosis Factor-alpha (physiology)