Pleiotrophin induces formation of functional neovasculature in vivo.
Pleiotrophin (PTN) is a heparin-binding growth/differentiation inducing cytokine that shares 50% amino acid sequence identity and striking domain homology with Midkine (MK), the only other member of the Ptn/Mk developmental gene family. The Ptn gene is expressed in sites of early vascular development in embryos and in healing wounds and its constitutive expression in many human tumors is associated with an angiogenic phenotype, suggesting that PTN has an important role in angiogenesis during development and in wound repair and advanced malignancies. To directly test whether PTN is angiogenic in vivo, we injected a plasmid to express PTN into ischemic myocardium in rats. Pleiotrophin stimulated statistically significant increases in both normal appearing new capillaries and arterioles each of which had readily detectable levels of the arteriole marker, smooth muscle cell alpha-actin. Furthermore, the newly formed blood vessels were shown to interconnect with the existent coronary vascular system. The results of these studies demonstrate directly that PTN is an effective angiogenic agent in vivo able to initiate new vessel formation that is both normal in appearance and function. The data suggest that PTN signals the more "complete" new blood vessel formation through its ability to stimulate different functions in different cell types not limited to the endothelial cell.
Christman
Karen L
KL
University of California Berkeley and San Francisco Joint Bioengineering Graduate Group, USA.
Fang
Qizhi
Q
Kim
Anne J
AJ
Sievers
Richard E
RE
Fok
Hubert H
HH
Candia
Albert F
AF
Colley
Kenneth J
KJ
Herradon
Gonzalo
G
Ezquerra
Laura
L
Deuel
Thomas F
TF
Lee
Randall J
RJ
D000818:Animals; D002196:Capillaries / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000502:physiology*; D018076:DNA, Complementary / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D007511:Ischemia; D008856:Microscopy, Fluorescence; D017202:Myocardial Ischemia; D009206:Myocardium / Q000473:pathology; D009389:Neovascularization, Pathologic; D016366:Open Reading Frames; D010477:Perfusion; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D014945:Wound Healing
D002352:Carrier Proteins; D016207:Cytokines; D018076:DNA, Complementary; C066845:pleiotrophin