Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis
| Autor: | Patrick H. Maxwell, Estelle Delamarre, Yukiji Takeda, Jens Serneels, Yoshihiko Saito, Andrey Anisimov, Mathias Wenes, Mario Leonardo Squadrito, Carmen Roncal, Kari Alitalo, Veronica Finisguerra, Massimiliano Mazzone, Sandra Costa, Michael Simons, Zhen W. Zhuang, Tapan Bhattacharyya, Rodrigo Leite de Oliveira, Michele De Palma, Bernard Gallez, Françoise Bruyère, Sofie Deschoemaeker, Bénédicte F. Jordan, Alexander Hamm, Julie Magat |
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| Přispěvatelé: | Cellular and Molecular Immunology |
| Předmět: |
Male
Necrosis Hindlimb 129 Strain Mice Smooth Muscle Ischemia Macrophage Myocyte Homeostasis Inbred BALB C Mice Inbred BALB C Arteries/growth & development Multidisciplinary NF-kappa B Arteries Cell biology medicine.anatomical_structure Phenotype Extremities/blood supply Female medicine.symptom Cardiology and Cardiovascular Medicine Procollagen-Proline Dioxygenase/deficiency Artery Heterozygote Mice 129 Strain Myocytes Smooth Muscle Procollagen-Proline Dioxygenase Myocytes Smooth Muscle/cytology Biology Article Hypoxia-Inducible Factor-Proline Dioxygenases Macrophages/metabolism medicine Animals Molecular Biology Ischemia/pathology Alleles Disease Models Animal Extremities Macrophages Myocytes Animal medicine.disease NF-kappa B/metabolism Immunology Disease Models Arteriogenesis |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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