α4β1 Integrin Mediates Selective Endothelial Cell Responses to Thrombospondins 1 and 2 In Vitro and Modulates Angiogenesis In Vivo

Maria J. Calzada, Longen Zhou, John M. Sipes, Jane Zhang, Henry C. Krutzsch, M. Luisa Iruela-Arispe, Douglas S. Annis, Deane F. Mosher, David D. Roberts*

*Corresponding author for this work

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

We examined the function of α4β1, integrin in angiogenesis and in mediating endothelial cell responses to the angiogenesis modulators, thrombospondin-1 and thrombospondin-2. α 4β1 supports adhesion of venous endothelial cells but not of microvascular endothelial cells on immobilized thrombospondin-1, vascular cell adhesion molecule-1, or recombinant N-terminal regions of thrombospondin-1 and thrombospondin-2. Chemotactic activities of this region of thrombospondin-1 and thrombospondin-2 are also mediated by α 4β1, whereas antagonism of fibroblast growth factor-2-stimulated chemotaxis is not mediated by this region. Immobilized N-terminal regions of thrombospondin-1 and thrombospondin-2 promote endothelial cell survival and proliferation in an α4β 1-dependent manner. Soluble α4β1 antagonists inhibit angiogenesis in the chick chorioallantoic membrane and neovascularization of mouse muscle explants. The latter inhibition is thrombospondin-1-dependent and not observed in explants from thrombospondin-1-/- mice. Antagonizing α4β 1 may in part block proangiogenic activities of thrombospondin-1 and thrombospondin-2, because N-terminal regions of thrombospondin-1 and thrombospondin-2 containing the α4β1 binding sequence stimulate angiogenesis in vivo. Therefore, α4β 1 is an important endothelial cell receptor for mediating motility and proliferative responses to thrombospondins and for modulation of angiogenesis.

Original languageEnglish (US)
Pages (from-to)462-470
Number of pages9
JournalCirculation research
Volume94
Issue number4
DOIs
StatePublished - Mar 5 2004

Keywords

  • Adhesion
  • Angiogenesis
  • Migration
  • Peptides
  • Proliferation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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