PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage1,2,3,4,5. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion6,7,8. We show that Phd2 (also known as Egln1) haplodeficient (Phd2+/−) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2+/− mice was due to an expansion of tissue-resident, M2-like macrophages9,10 and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2+/− macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.
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This work was supported by grants from FWO (G.0726.10), Belgium, and from VIB. The authors are thankful to P. Carmeliet for the Phd2 KO and cKO mice, M. Karin for the Ikbkb cKO mice, P. Ratcliffe for the PHD2H313A construct, A. Luttun and P. Fazzari for comments, Y. Jonsson and T. Janssens for technical assistance. VE-Cadherin:CreERT and PDGFRB:Cre transgenic mice were generated at Cancer Research UK and kindly donated by R. Adams. E.D. was funded by ARC, S.C. by FCT, R.L.O. and V.F. by FWO, A.H. by DFG. C.R. was supported by COST action TD0901. M.D.P. was supported by an ERC starting grant.
The authors declare no competing financial interests.
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Takeda, Y., Costa, S., Delamarre, E. et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479, 122–126 (2011). https://doi.org/10.1038/nature10507
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