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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080584-02
Application #
7179336
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$400,538
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Vartanian, Shant M; Sarkar, Rajabrata (2007) Therapeutic angiogenesis. Vasc Endovascular Surg 41:173-85