Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation.
Eph/ephrin signaling is pivotal in prenatal angiogenesis while its potential role in postnatal angiogenesis largely remains to be explored. Therefore its putative angiogenic and therapeutic effects were explored in endothelium and in myocardial ischemia. In culture of human aortic endothelial cells the fusion protein ephrinB2-Fc induced cell proliferation (p<0.0005) and in the murine aortic ring model ephrinB2-Fc induced increased sprouting (p<0.05). Myocardial infarction was induced by ligation of the left anterior descending artery in mouse. During the following 2 weeks mRNA of the receptor/ligand pair EphB4/ephrinB2 was expressed dichotomously (p<0.05) and other Eph/ephrin pairs were expressed to a lesser degree. Twenty-four hours after intraperitoneal administration of ephrinB2-Fc it was detected in abundance throughout the myocardium along capillaries, showing signs of increased mitosis. After 4 weeks the capillary density was increased 28% in the periinfarcted area (p<0.05) to a level not different from healthy regions of the heart where no change was observed. These results implicate that EphB4/ephrinB2 is an important signaling pathway in ischemic heart disease and its modulation may induce therapeutic angiogenesis.
Department of Cardiology, Karolinska University Hospital, Karolinska Institute, S141 86 Stockholm, Sweden.
Agneta
A
Månsson-Broberg
Anwar J
AJ
Siddiqui
Maria
M
Genander
Karl-Henrik
KH
Grinnemo
Xiaojin
X
Hao
Agneta B
AB
Andersson
Eva
E
Wärdell
Christer
C
Sylvén
Matthias
M
Corbascio
D000818:Animals; D001011:Aorta; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D036388:Ephrin-B2; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins