During the neovascularization process associated with physiologic as well as pathologic states, a variety of growth factors initiate an angiogenic response which induces endothelial cells to cross their underlying basement membrane and to infiltrate the surrounding interstitial matrix. The collagen-fibrin matrix then acts as a substratum for ingressing blood vessels. Concurrently, angiogenic growth factors such as VEGF, working alone or in combination with other growth factors, regulates the expression of endothelial cell adhesion molecules and proteinases which allow the cells to penetrate collagen/fibrin barriers, and undergo a tubulogenic program. While a range of anti-angiogenic therapeutics have shown promising effects in animal models - and even in humans - with regard to disease states associated with tumorigenesis/metastasis as well as inflammation, little is known with regard either to the identity of the proteinases that regulate the development of neovessels at pathologic sites, or the factors that regulate their expression. Indeed, whereas a number of collagenolytic and fibrinolytic cascades have been posited to play a critical role in angiogenesis, we have recently identified a small family of membrane-anchored metalloproteinases that appear to play a dominant role in driving blood vessel formation. Based on new findings which support a role for MT1-MMP in basement membrane invasion, endothelial cell invasion and proliferation as well as morphogenesis, we propose to i) Define the role of MT1-MMP in endothelial cell-mediated basement membrane degradation and perforation, ii) characterize the role of MT1-MMP in basement membrane turnover during in vivo angiogenesis, iii) define the growth regulatory properties of endothelial cell MT1-MMP, iv) characterize the morphogen-inducing properties of MT1-MMP that regulate neovessel formation and v) compare and contrast the proteolytic machinery mobilized by lymphatic endothelium that drive invasion, proliferation and branching tubulogenesis. Together, the outlined studies should help establish the basic mechanisms by which proteinases regulate neovessel growth during physiologic as well as pathologic states, and may assist in the identification of new targets for intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA088308-06
Application #
6969513
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Macleod, Carol L
Project Start
2000-07-06
Project End
2010-04-30
Budget Start
2005-07-06
Budget End
2006-04-30
Support Year
6
Fiscal Year
2005
Total Cost
$316,942
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gómez-Escudero, Jesús; Moreno, Vanessa; Martín-Alonso, Mara et al. (2017) E-cadherin cleavage by MT2-MMP regulates apical junctional signaling and epithelial homeostasis in the intestine. J Cell Sci 130:4013-4027
Lin, Yongshun; Li, Xiao-Yan; Willis, Amanda L et al. (2014) Snail1-dependent control of embryonic stem cell pluripotency and lineage commitment. Nat Commun 5:3070
Wu, Zhao-Qiu; Rowe, R Grant; Lim, Kim-Chew et al. (2014) A Snail1/Notch1 signalling axis controls embryonic vascular development. Nat Commun 5:3998
Morell, Montse; Nguyen Duc, Thinh; Willis, Amanda L et al. (2013) Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity. J Am Chem Soc 135:9139-48
Willis, A L; Sabeh, F; Li, X-Y et al. (2013) Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. J Microsc 251:250-60
Wolf, Katarina; Te Lindert, Mariska; Krause, Marina et al. (2013) Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol 201:1069-84
Koenig, Gerald C; Rowe, R Grant; Day, Sharlene M et al. (2012) MT1-MMP-dependent remodeling of cardiac extracellular matrix structure and function following myocardial infarction. Am J Pathol 180:1863-78
Shimizu-Hirota, Ryoko; Xiong, Wanfen; Baxter, B Timothy et al. (2012) MT1-MMP regulates the PI3K?·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev 26:395-413
Kim, Nam Hee; Kim, Hyun Sil; Kim, Nam-Gyun et al. (2011) p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal 4:ra71
Matus, David Q; Li, Xiao-Yan; Durbin, Sarah et al. (2010) In vivo identification of regulators of cell invasion across basement membranes. Sci Signal 3:ra35

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