Journal Article

Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis

Alitalo, Kari, Zhuang, Zhen W., Jordan, Benedicte F., Saito, Yoshihiko, Mazzone, Massimiliano, Deschoemaeker, Sofie, Anisimov, Andrey, Delamarre, Estelle, Takeda, Yukiji, Costa, Sandra, Wenes, Mathias, Simons, Michael, Squadrito, Mario Leonardo, Serneels, Jens, Magat, Julie, Hamm, Alexander, Maxwell, Patrick, De Palma, Michele, Bhattacharyya, Tapan, Leite de Oliveira, Rodrigo, Finisguerra, Veronica, Bruyère, Françoise, Roncal, Carmen, Gallez, Bernard

2011

Overview

Blood-supply boost in ischaemia The cellular oxygen-sensing enyzme PHD2 uses oxygen to degrade hypoxia-inducible factor 1α. Using a mouse model of limb ischaemia, Takeda et al . link oxygen sensing through PHD2 to macrophage phenotype and arteriogenesis. They show that myeloid-cell-specific PHD2 haplodeficiency results in improved arteriogenesis after ischaemia owing to hyperactivation of NFκB signalling in the macrophages and the promotion of an M2-like repair phenotype. This suggests that PHD2 inhibition might promote collateral vascularization in patients who are at risk of limb or heart ischaemia. PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage 1 , 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 occlusion 6 , 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 macrophages 9 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2504/342 / 631/250/516/1909 / 631/443/592 / 631/443/592/1939 / Alleles / Angiogenesis / Animals / Arteries - growth & development / Biological and medical sciences / Care and treatment / Classical genetics, quantitative genetics, hybrids / Diagnosis / Disease Models, Animal / Extremities - blood supply / Extremities - pathology / Female / Fundamental and applied biological sciences. Psychology / Genetics of eukaryotes. Biological and molecular evolution / Genotype & phenotype / Heterozygote / Homeostasis / Humanities and Social Sciences / Hypoxia-Inducible Factor-Proline Dioxygenases / Ischemia / Ischemia - pathology / Ischemia - prevention & control / letter / Macrophages / Macrophages - metabolism / Male / Medical imaging / Mice / Mice, 129 Strain / Mice, Inbred BALB C / multidisciplinary / Myocytes, Smooth Muscle - cytology / Necrosis / Neovascularization / NF-kappa B - metabolism / Oxidative stress / Phenotype / Physiological aspects / Prevention / Procollagen-Proline Dioxygenase - deficiency / Procollagen-Proline Dioxygenase - genetics / Procollagen-Proline Dioxygenase - metabolism / Rodents / Science / Science (multidisciplinary) / Veins & arteries / Vertebrata / Wound healing