Kallistatin is a new inhibitor of angiogenesis and tumor growth.
Kallistatin is a unique serine proteinase inhibitor (serpin) and a heparin-binding protein. It has been localized in vascular smooth muscle cells and endothelial cells of human blood vessels, suggesting that kallistatin may be involved in the regulation of vascular function. Our previous study showed that kallistatin plays a role in neointima hyperplasia. In this study, we investigated the potential role of kallistatin in angiogenesis in vitro and in vivo. Purified human kallistatin significantly inhibited vascular endothelial growth factor (VEGF)- or basic fibroblast growth factor (bFGF)-induced proliferation, migration, and adhesion of cultured endothelial cells. Kallistatin attenuated VEGF- or bFGF-induced capillary density and hemoglobin content in subcutaneously implanted Matrigel plugs in mice. To further investigate the role of kallistatin in angiogenesis, we prepared adenovirus carrying the human kallistatin cDNA (Ad.HKBP) and evaluated the effect of kallistatin gene delivery on spontaneous angiogenesis in a rat model of hind-limb ischemia. Local kallistatin gene delivery significantly reduced capillary formation and regional blood perfusion recovery in the ischemic hind limb after removal of the femoral artery. Furthermore, a single intratumoral injection of Ad.HKBP into pre-established human breast tumor xenografts grown in athymic mice resulted in significant inhibition of tumor growth. CD31 immunostaining of tumor sections showed a decreased number of blood vessels in the kallistatin-treated group as compared to the control. These results demonstrate a novel role of kallistatin in the inhibition of angiogenesis and tumor growth.
Miao
Robert Q
RQ
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Agata
Jun
J
Chao
Lee
L
Chao
Julie
J
D000230:Adenocarcinoma / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D004343:Drug Implants; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005822:Genetic Vectors / Q000008:administration & dosage; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D015552:Injections, Intralesional; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology; D008222:Lymphokines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009389:Neovascularization, Pathologic / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D018076:DNA, Complementary; D004343:Drug Implants; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C051324:kallistatin; D016222:Fibroblast Growth Factor 2