title: Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis.
abstract: PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. 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 occlusion. 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 macrophages 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.
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors: Yukiji
authors: Y
authors: Takeda
authors: Sandra
authors: S
authors: Costa
authors: Estelle
authors: E
authors: Delamarre
authors: Carmen
authors: C
authors: Roncal
authors: Rodrigo
authors: R
authors: Leite de Oliveira
authors: Mario Leonardo
authors: ML
authors: Squadrito
authors: Veronica
authors: V
authors: Finisguerra
authors: Sofie
authors: S
authors: Deschoemaeker
authors: Françoise
authors: F
authors: Bruyère
authors: Mathias
authors: M
authors: Wenes
authors: Alexander
authors: A
authors: Hamm
authors: Jens
authors: J
authors: Serneels
authors: Julie
authors: J
authors: Magat
authors: Tapan
authors: T
authors: Bhattacharyya
authors: Andrey
authors: A
authors: Anisimov
authors: Benedicte F
authors: BF
authors: Jordan
authors: Kari
authors: K
authors: Alitalo
authors: Patrick
authors: P
authors: Maxwell
authors: Bernard
authors: B
authors: Gallez
authors: Zhen W
authors: ZW
authors: Zhuang
authors: Yoshihiko
authors: Y
authors: Saito
authors: Michael
authors: M
authors: Simons
authors: Michele
authors: M
authors: De Palma
authors: Massimiliano
authors: M
authors: Mazzone
mesh_terms: D000483:Alleles; D000818:Animals; D001158:Arteries / Q000254:growth & development*; D004195:Disease Models, Animal; D005121:Extremities / Q000098:blood supply* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006706:Homeostasis; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases