Mechanisms of MMP-2 transcription in hindlimb ischemia

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DESCRIPTION (provided by applicant): Critical ischemia of the lower limbs remains a serious problem in vascular surgery with a substantial fraction of patients undergoing eventual amputation despite surgical bypass and catheter-directed therapies. The cellular and molecular mechanisms that drive in vivo transcription of genes essential for correction of ischemia remain largely undefined, and are a potential area for the development of therapeutic regimens for tissue ischemia. Matrix metalloproteinases are enzymes critical for angiogenesis and arteriogenesis induced by tissue ischemia. Matrix metalloproteinase 2 (MMP-2) is transcriptionally induced in tissue ischemia and is a critical enzyme for angiogenesis and arterial enlargement. The molecular mechanisms for transcriptional induction of MMP-2 and the significance of MMP-2 upregulation in ischemia in vivo remain unknown. Therefore, we propose to test the central hypotheses of this proposal: Tissue ischemia induces MMP-2 transcription via specific cis- and trans-acting regulatory elements and MMP-2 expression plays a critical role in the angiogenesis and arteriogenesis induced by ischemia. This hypothesis will be tested with the following Specific Aims: 1) To determine the regions within the MMP-2 promoter that are critical for in vivo transcriptional activation by ischemia, 2) To identify the transcription factors responsible for ischemia-induced MMP-2 transcription in vivo and characterize their activation by specific mediators in vivo, 3) To determine if MMP-2 is critical to the revascularization response after ischemia and to examine the effect of cell type-specific overexpression of MMP-2 on ischemia-induced angiogenesis and arteriogenesis in vivo. Defining the cellular and molecular mechanisms that induce MMP-2 expression in vivo will increase our knowledge of transcriptional activation of critical genes by tissue ischemia, and form the foundation for the development of molecular therapy for critical limb ischemia in patients.