IP-10 induces dissociation of newly formed blood vessels.
The signals that prune the exuberant vascular growth of tissue repair are still ill defined. We demonstrate that activation of CXC chemokine receptor 3 (CXCR3) mediates the regression of newly formed blood vessels. We present evidence that CXCR3 is expressed on newly formed vessels in vivo and in vitro. CXCR3 is expressed on vessels at days 7-21 post-wounding, and is undetectable in unwounded or healed skin. Treatment of endothelial cords with CXCL10 (IP-10), a CXCR3 ligand present during the resolving phase of wounds, either in vitro or in vivo caused dissociation even in the presence of angiogenic factors. Consistent with this, mice lacking CXCR3 express a greater number of vessels in wound tissue compared to wild-type mice. We then hypothesized that signaling from CXCR3 not only limits angiogenesis, but also compromises vessel integrity to induce regression. We found that activation of CXCR3 triggers micro-calpain activity, causing cleavage of the cytoplasmic tail of beta3 integrins at the calpain cleavage sites c'754 and c'747. IP-10 stimulation also activated caspase 3, blockage of which prevented cell death but not cord dissociation. This is the first direct evidence for an extracellular signaling mechanism through CXCR3 that causes the dissociation of newly formed blood vessels followed by cell death.
Bodnar
Richard J
RJ
Pittsburgh Veterans Affairs Medical Center, Pittsburgh, PA 15240, USA. rjb8@pitt.edu
Yates
Cecelia C
CC
Rodgers
Margaret E
ME
Du
Xiaoping
X
Wells
Alan
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002154:Calpain / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D054367:Receptors, CXCR3 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D002154:Calpain; C449002:mu-calpain