Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis.
OBJECTIVE
Neuregulins (NRG) are growth factors that are synthesized by endothelial cells (ECs) and bind to erbB receptors. We have shown previously that NRG is proangiogenic in vitro, and that NRG/erbB signalling is important for autocrine endothelial angiogenic signalling in vitro. However, the role of NRG in the angiogenic response to ischaemia is unknown. We hypothesized that endothelial NRG is required for ischaemia-induced angiogenesis in vivo and that exogenous administration of NRG will enhance angiogenic responses after ischaemic insult.


RESULTS
An endothelial-selective inducible NRG knockout mouse was created and subjected to femoral artery ligation. Endothelial NRG deletion significantly decreased blood flow recovery (by 40%, P < 0.05), capillary density, α(v)β(3) integrin activation, and arteriogenesis after ischaemic injury. Isolated ECs from knockout mice demonstrated significantly impaired cord formation in vitro, suggesting that NRG signalling performs an important cell autonomous function. Recombinant human NRG (rNRG) has not only reversed the angiogenic defect in knockout mice but also accelerated blood flow recovery in wild-type mice.


CONCLUSIONS
Endothelial production of NRG is required for angiogenesis and arteriogenesis induced by ischaemic injury. Furthermore, exogenous administration of rNRG can enhance this process, suggesting a potential role for NRG in vascular disease.
Department of Internal Medicine, Section of Cardiovascular Medicine,  Yale School of Medicine, New Haven, CT,  USA.
Nadia
N
Hedhli
Lawrence W
LW
Dobrucki
April
A
Kalinowski
Zhen W
ZW
Zhuang
Xiaohong
X
Wu
Raymond R
RR
Russell
Albert J
AJ
Sinusas
Kerry S
KS
Russell
D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001672:Biocompatible Materials; D002455:Cell Division / Q000502:physiology; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005263:Femoral Artery / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism*; D007797:Laminin; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology
D001672:Biocompatible Materials; D004338:Drug Combinations; D039302:Integrin alphaVbeta3; D007797:Laminin; C094131:NRG1 protein, human; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011509:Proteoglycans; D011994:Recombinant Proteins; C059485:matrigel; D003094:Collagen