Abstract
Vascular endothelial cells produce considerable amounts of matrix metalloproteinases (MMP), including MMP-2, MMP-9, and membrane type 1 (MT1)-MMP. However, little is known about the regulatory mechanisms of these protease activities exhibited during vascular development. A glycosylphosphatidylinositol-anchored glycoprotein, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), has been shown to attenuate MMP-2 maturation by directly interacting with MT1-MMP. Here, we show that an angiogenic factor angiopoietin-1 induces RECK expression in human umbilical vein endothelial cells (HUVEC), and RECK depletion in these cells results in defective vascular tube formation and cellular senescence. We further observed that RECK depletion downregulates beta1-integrin activation, which was associated with decreased autophosphorylation of focal adhesion kinase and increased expression of a cyclin-dependent kinase inhibitor p21(CIP1). In agreement, significant downregulation of beta1-integrin activity was observed in vascular endothelial cells in Reck-/- mouse embryos. In HUVECs, specific inhibition of MMP-2 significantly antagonized the effect of RECK depletion on beta1-integrin signaling, cell proliferation, and tube elongation. Furthermore, we observed that hypervascular tumor-derived cell lines can induce high RECK expression in convoluted vascular endothelial cells, and this in turn supports tumor growth. Targeting RECK specifically in tumor-associated vascular endothelial cells resulted in tumor regression. Therefore, we propose that RECK in tumor vascular endothelial cells can be an interesting target of cancer treatment via abortion of tumor angiogenesis.
Highlights
MMPs are Ca++ and Zn++-dependent endopeptidases that play crucial roles in the degradation of various extracellular matrix (ECM) components [1]
RECK is involved in the development of vascular endothelial cells, we first examined the effects of various angiogenic factors on the transcriptional regulation of RECK in human umbilical vein endothelial cells (HUVECs) cultured in EBM-2
This study revealed that RECK expression in HUVECs was induced by angiopoietin-1, but not by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) or epidermal growth factor (EGF) (Fig. 1A), suggesting that RECK expression is regulated in vascular endothelial cells by a specific angiogenic factor
Summary
MMPs are Ca++ and Zn++-dependent endopeptidases that play crucial roles in the degradation of various extracellular matrix (ECM) components [1]. Other anti-angiogenic functions of MMPs include generation of cryptic angiogenesis inhibitors from plasminogen or collagens, such as angiostatin, endostatin, tumstatin, arrestin or canstatin; all of these are supposed to exert their anti-angiogenic functions by interacting with various forms of integrins including α5β1, αvβ, α1β1 and α3β1 [5,6]. Soluble hemopexin (PEX) domain derived from degraded MMP-2 blocks the binding of intact MMP-2 to integrin αvβ3 [7]. These findings suggest that the anti-angiogenic functions of MMPs profoundly involve integrin signaling
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