Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo.
We examined the function of alpha4beta1 integrin in angiogenesis and in mediating endothelial cell responses to the angiogenesis modulators, thrombospondin-1 and thrombospondin-2. Alpha4beta1 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 alpha4beta1, 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 alpha4beta1-dependent manner. Soluble alpha4beta1 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 alpha4beta1 may in part block proangiogenic activities of thrombospondin-1 and thrombospondin-2, because N-terminal regions of thrombospondin-1 and thrombospondin-2 containing the alpha4beta1 binding sequence stimulate angiogenesis in vivo. Therefore, alpha4beta1 is an important endothelial cell receptor for mediating motility and proliferative responses to thrombospondins and for modulation of angiogenesis.
Calzada
Maria J
MJ
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Md 20892-1500, USA.
Zhou
Longen
L
Sipes
John M
JM
Zhang
Jane
J
Krutzsch
Henry C
HC
Iruela-Arispe
M Luisa
ML
Annis
Douglas S
DS
Mosher
Deane F
DF
Roberts
David D
DD
D000818:Animals; D002196:Capillaries / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D006801:Humans; D007084:Iliac Vein; D039041:Integrin alpha4beta1 / Q000502:physiology*; D008168:Lung; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009928:Organ Specificity; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin; D019700:Thrombospondin 1 / Q000737:chemistry / Q000172:deficiency / Q000494:pharmacology*; D019699:Thrombospondins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology; D000099262:Thrombospondin 2
D016222:Fibroblast Growth Factor 2; D039041:Integrin alpha4beta1; D010446:Peptide Fragments; D012333:RNA, Messenger; D019700:Thrombospondin 1; D019699:Thrombospondins; D019010:Vascular Cell Adhesion Molecule-1; D000099262:Thrombospondin 2