Macrophage Skewing by Phd2 Haplodeficiency Prevents Ischaemia by Inducing Arteriogenesis

Overview

Journal Nature

Specialty Science

Date 2011 Oct 11

PMID 21983962

Citations 150

Authors

Yukiji Takeda

Sandra Costa

Estelle Delamarre

Carmen Roncal

Rodrigo Leite de Oliveira

Mario Leonardo Squadrito

Veronica Finisguerra

Sofie Deschoemaeker

Francoise Bruyere

Mathias Wenes

Alexander Hamm

Jens Serneels

Julie Magat

Tapan Bhattacharyya

Andrey Anisimov

Benedicte F Jordan

Kari Alitalo

Patrick Maxwell

Bernard Gallez

Zhen W Zhuang

Yoshihiko Saito

Michael Simons

Michele de Palma

Massimiliano Mazzone

Affiliations

Soon will be listed here.

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.

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