Type I collagen is a molecular target for inhibition of angiogenesis by endogenous thrombospondin-1.

Abstract:

:Three-dimensional explant cultures of muscle tissue were used to characterize secreted proteins regulated by endogenous levels of the angiogenesis modulator thrombospondin (TSP)-1. Explants from TSP1 null mice exhibit enhanced neovascularization associated with increased endothelial outgrowth but decreased outgrowth of perivascular smooth muscle cells . The absence of endogenous TSP1 did not diminish activation of latent transforming growth factor-beta and moderately decreased matrix metalloproteinase levels. However, significant changes in other secreted proteins were observed. Endogenous TSP1 decreased mRNA levels for collagens Ialpha1, Ialpha2, and IIIalpha1 and laminin alpha4 and increased collagen IValpha1 mRNA expression. Endogenous TSP1 also decreased the level of type I collagen protein produced by the vascular outgrowths. Collagens Ialpha1, Ialpha2, and IIIalpha1 are known tumor endothelial markers, suggesting that TSP1 coordinately regulates a set of extracellular matrix genes that reverse the angiogenic switch. Suppression of collagen Ialpha1 or Ialpha2 mRNAs using antisense morpholinos inhibited outgrowth in TSP1 null explants and proliferation of TSP1 null endothelial cells, indicating that type I collagen synthesis is limiting for this neovascularization response.

journal_name

Oncogene

journal_title

Oncogene

authors

Zhou L,Isenberg JS,Cao Z,Roberts DD

doi

10.1038/sj.onc.1209069

subject

Has Abstract

pub_date

2006-01-26 00:00:00

pages

536-45

issue

4

eissn

0950-9232

issn

1476-5594

pii

1209069

journal_volume

25

pub_type

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