Submitted on January 14, 2009
Revised on May 13, 2009
Accepted on May 28, 2009
Vascular Regression and Survival are Differentially Regulated by MT1-MMP and TIMPs in the Aortic Ring Model of Angiogenesis
Alfred C. Aplin1, Wen-Hui Zhu1, Eric Fogel2, and Roberto F. Nicosia2*
1 University of Washington
2 VA Puget Sound Health Care System
* To whom correspondence should be addressed. E-mail: roberto.nicosia{at}va.gov.
This study was designed to investigate the role of MMPs and 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 MT1-MMP (MMP14). Vascular growth and regression were not affected by disruption of MMP-2 or MMP-9 genes. Conversely angiogenesis was blocked and vessels stabilized by inhibiting MMP14 with neutralizing antibodies, TIMP-2, TIMP-3 or TIMP-4. TIMP-1 which blocks MMP2 and MMP9 but is a poor inhibitor of MT1-MMP had no anti-angiogenic 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 anti-collagenolytic 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.
