VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation Journal Article


Authors: Chang, S. H.; Kanasaki, K.; Gocheva, V.; Blum, G.; Harper, J.; Moses, M. A.; Shih, S. C.; Nagy, J. A.; Joyce, J.; Bogyo, M.; Kalluri, R.; Dvorak, H. F.
Article Title: VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation
Abstract: Tumors initiate angiogenesis primarily by secreting vascular endothelial growth factor (VEGF-A<sup>164</sup>). The first new vessels to form are greatly enlarged, pericyte-poor sinusoids, called mother vessels (MV), that originate from preexisting venules. We postulated that the venular enlargement necessary to form MV would require a selective degradation of their basement membranes, rigid structures that resist vascular expansion. To identify the specific proteases responsible for MV formation, we induced angiogenesis in mouse tissues with an adenoviral vector expressing VEGF-A<sup>164</sup> (Ad-VEGF-A <sup>164</sup>) or with VEGF-A-secreting TA3/St mammary tumors. We found that MV formation resulted from greatly increased activity of cathepsins (B&gt;Sm&gt;L) in venules transitioning into MV, as well as from a reciprocal decrease in the expression of several cysteine protease inhibitors (CPI), stefin A and cystatins B and C, by these same venules. Using a fluorescence probe that selectively binds cellular sites of cathepsin protease activity in vivo, we showed that increased cathepsin activity was localized exclusively to perivenular cells, not to venule endothelial cells. CPI strikingly inhibited angiogenesis in the Matrigel assay, and Ad-VEGF-A<sup>164</sup>-induced angiogenesis was reduced by ∼50% in cathepsin B-null mice. Thus, VEGF-A, whether expressed by interstitial cells infected with an adenoviral vector or by tumor cells, upsets the normal cathepsin-CPI balance in nearby venules, leading to degradation of their basement membranes, an important first step in angiogenesis. ©2009 American Association for Cancer Research.
Keywords: controlled study; protein expression; vascular endothelial growth factor a; nonhuman; polymerase chain reaction; protein localization; neoplasms; animal cell; mouse; animals; mice; mice, knockout; animal tissue; basement membrane; fluorescence; protein binding; enzyme activity; cysteine proteinase inhibitors; angiogenesis; neovascularization, pathologic; leydig cell; endothelium cell; mice, nude; breast tumor; vasculotropin a; tumor cell; blood vessel; protein induction; adenovirus vector; cathepsin; cathepsin b; cystatin b; cystatin c; cysteine proteinase inhibitor; matrigel; proteinase; stefin a; venule; cathepsins; cystatin a; microcirculation; venules
Journal Title: Cancer Research
Volume: 69
Issue: 10
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2009-05-15
Start Page: 4537
End Page: 4544
Language: English
DOI: 10.1158/0008-5472.can-08-4539
PUBMED: 19435903
PROVIDER: scopus
PMCID: PMC2683911
DOI/URL:
Notes: --- - "Cited By (since 1996): 5" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"
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MSK Authors
  1. Johanna A Joyce
    67 Joyce
  2. Vasilena Gocheva
    15 Gocheva