Related Experiment Video
Updated: Jun 22, 2026
Aortic Ring Assay
Published on: November 24, 2009
Vascular regression and survival are differentially regulated by MT1-MMP and TIMPs in the aortic ring model of
Abstract:
This study was designed to investigate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the reabsorption of neovessels in collagen gel cultures of rat and mouse aortic rings. Aortic angiogenesis was associated with collagen lysis and production of the matrix-degrading enzymes MMP-2, MMP-9, and membrane-type MMP (MT1-MMP, or MMP-14). Vascular growth and regression were not affected by disruption of MMP-2 or MMP-9. In addition, no effect on vascular regression was observed by blocking plasmin, a protease implicated in the activation of MMPs, with epsilon-aminocaproic acid or by adding plasminogen, which caused a modest increase in vascular proliferation. Conversely, angiogenesis was blocked and vessels stabilized by inhibiting MT1-MMP with neutralizing antibodies, TIMP-2, TIMP-3, or TIMP-4. TIMP-1, which blocks MMP-2 and MMP-9 but is a poor inhibitor of MT1-MMP, had no antiangiogenic effect. However, TIMP-1 prolonged the survival of neovessels following angiogenesis. Vascular regression was accelerated in aortic cultures from TIMP-1- and TIMP-2-deficient mice. The vascular survival effect of anti-MT1-MMP antibodies and TIMPs with MT1-MMP inhibitory activity was associated with complete inhibition of collagen lysis. In contrast, TIMP-1 had no anticollagenolytic effect. These results indicate that MT1-MMP plays a critical role not only in angiogenesis but also in vascular regression and demonstrate that TIMPs with anti-MT1-MMP activity have opposite effects on angiogenic outcomes depending on the stage of the angiogenic process. This study also suggests the existence of a TIMP-1-mediated alternate pathway of vascular survival that is unrelated to MT1-MMP inhibitory activity.
Insights
Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are key in blood vessel remodeling. Membrane-type MMP (MT1-MMP) is crucial for both blood vessel growth and regression, while TIMP-1 offers an alternative survival pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Vascular Biology
Background:
- Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) regulate extracellular matrix remodeling.
- Angiogenesis, the formation of new blood vessels, involves complex enzymatic processes.
- Vascular regression, the breakdown of blood vessels, is also mediated by specific enzymes.
Purpose of the Study:
- To investigate the roles of MMPs and TIMPs in neovascularization and regression in aortic ring cultures.
- To determine the specific functions of MMP-2, MMP-9, and MT1-MMP in vascular development and breakdown.
- To elucidate the impact of various TIMPs on angiogenic processes and vascular survival.
Main Methods:
- Collagen gel cultures of rat and mouse aortic rings were used to model angiogenesis and vascular regression.
- Enzyme activity was assessed through collagen lysis measurements.
- Inhibition of specific MMPs and proteases was achieved using neutralizing antibodies, specific inhibitors, and gene-deficient models.
Main Results:
- Aortic angiogenesis correlated with collagen degradation and the production of MMP-2, MMP-9, and MT1-MMP.
- Disrupting MMP-2 or MMP-9 did not affect vascular growth or regression.
- Inhibition of MT1-MMP, but not MMP-2 or MMP-9, blocked angiogenesis and stabilized vessels, indicating MT1-MMP's critical role.
- TIMP-1 did not inhibit angiogenesis but prolonged neovessel survival, suggesting an alternative pathway.
- Vascular regression was accelerated in TIMP-1 and TIMP-2 deficient mice.
Conclusions:
- MT1-MMP is essential for both angiogenesis and vascular regression, playing a dual role in blood vessel remodeling.
- TIMPs targeting MT1-MMP activity can have opposing effects on angiogenesis depending on the stage.
- A TIMP-1-dependent pathway exists for vascular survival independent of MT1-MMP inhibition.
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:10Mechanism of Angiogenesis