**1. Introduction**

Arteriogenesis is the process by which a pre-existing arterioarterial anastomosis develops into a functional collateral network following an arterial occlusion. The remodeling processes involved in collateral vessel growth are complex and are dependent on mechanical, cellular and molecular factors [1]. Several authors have demonstrated the pertinence of monocytes and macrophages in enhancing collateral vessel growth [1–3]. While there is still debate over whether perivascular macrophages are recruited from circulating monocytes or tissue resident precursors, their proarteriogenic e ffects, however, are still evident [4–6]. Macrophage activation types have become a growing focus in arteriogenesis research, in particular alternatively activated macrophages [7]. Macrophage heterogeneity and

plasticity are reflected by their ability to respond to environmental cues giving rise to a spectrum of distinct functional phenotypes or activation states, fulfilling a variety of functions. The extremes of these functional states are commonly defined as M1, M2, or M2-like polarized macrophages [8]. M1 or classically activated macrophages induced by LPS, IFN-γ, and TNF are associated with inflammation and tumor resistance. They di ffer from M2 macrophages with regard to their arginine metabolism by exhibiting high levels of iNOS and subsequent NO-synthesis, as well as the production of proinflammatory cytokines and chemoattractant proteins. M2/M2-like or alternatively activated macrophages induced by IL4/IL13, immune complexes, agonists of TLR or IL1R, glucocorticoids and IL10, on the other hand, regulate inflammatory responses and promote tissue remodeling, angiogenesis and tumor progression [9]. They are characterized by their arginase/ornithine production, a precursor of cell proliferation, collagen production and ECM remodeling, and the production of anti-inflammatory cytokines [9,10]. While both M1 and M2 macrophages have been shown to contribute to collateral vessel growth, a systemic modulation of known activators of macrophage di fferentiation demonstrated a determinate proarteriogenic role of M2 macrophages induced by IL10 [11]. This M2 activation phenotype, also referred to as M2c, not only acts as a regulator of immune responses but also as an effector cell of tissue remodeling and repair [9]. It is important to note that the M1/M2 taxonomy of macrophages only represents a limited attempt to categorize the vast variety of functional states observed in vitro. In vivo, this M1/M2 paradigm undermines the complexity of macrophage plasticity and diversity. Functional and phenotypical characteristics of M1 and M2 activation states are not limited to but may instead be shared by more than one macrophage population, allowing them to cater to situational and tissue specific needs. This dogma change has created the need to explore other classifications that more appropriately reflect macrophage behavior in vivo and are subject of current research [12]. Jetten et al. [6] showed that collateral growth was una ffected in mice with a deletion of the IL10 receptor on myeloid cells (IL10Rfl/fl/LysMCre+), arguing that the M2c activation phenotype is not required in arteriogenesis. When treated with exogenously polarized M2c macrophages, however, an improved reperfusion of collateral vessels compared to untreated IL10Rfl/fl/LysMCre<sup>+</sup> mice was still observed. As such, this study investigates the in vivo effect of varying levels of IL10 on arteriogenesis as well as the distribution of macrophage activation types around growing collateral vessels.
