Chronic arterial occlusion leads to growth of collaterals - a process termed arteriogenesis, in which macrophages play a prominent role in remodelling and growth. However, a detailed analysis which of distinct macrophage subpopulations involved in arteriogenesis has never been performed. In the present study the temporal and spatial distribution of macrophage subtypes during arteriogenesis in a rat model with chronically elevated fluid shear stress (FSS) is investigated. Local macrophage subpopulations were histologically immuno-phenotyped using CD68 (a ubiquitous macrophage marker) and CD163, a specific M2 macrophage marker. Without occlusion few M2-macrophages reside in the perivascular space. Early after occlusion (12h) the number of M2 macrophages increases strongly and M1 macrophages begin emerging into the collateral. After 3 days they appear in the perivascular space. Both macrophage subtypes increase until 28d after treatment, whereas M2 macrophages dominate at the site of collateral growth. The local distribution of the subpopulations changes during the arteriogenic process. Whereas M1 macrophages are detected directly adjacent to the media, M2 macrophages are present in the most outer perivascular region of the growing collateral vessel. Systemic alterations of blood leucocytes in mice after femoral artery ligature (FAL) were investigated by FACS analysis of serial blood samples. During collateral remodelling histological changes were not reflected in circulating monocytes in the peripheral blood. The activation state of macrophages in mice with FAL was modulated by injections of either dexamethasone or the interleukins IL10 or IL3/IL14. The arteriogenic response was assessed by hind limb perfusion with laser Doppler measurements after 3, 7 and 14d. Suppressing inflammatory monocyte subtypes (M1) with dexamethasone led to impaired perfusion recovery after FAL in mice, whereas IL10 or IL4/IL13 application significantly increased perfusion recovery. This investigation demonstrates that a forced shift towards M2 macrophages improves the arteriogenic response. The distinct early increase and spatial distribution of M2 macrophages support the idea that this subtype plays a predominant role during collateral remodelling.

Rationale: Positive outward remodeling of pre-existing collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent cardiovascular ischemia. Collateral arterial growth is accompanied by expression of kinin precursor. However, the role of kinin signaling via the kinin receptors (B1R and B2R) in arteriogenesis is unclear.Objective: The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis. Key Words: bone marrow transplantation Ⅲ bradykinin receptors Ⅲ collateral growth Ⅲ leukocytes A rteriogenesis is the process that involves the flow-induced outward remodeling of preexisting collateral arterial pathways into functional conductance arteries (biological bypass). As a result of the arteriogenesis process, blood perfusion to the compromised region is restored; 1 therefore, it is regarded as a clinically highly relevant target. It is established that arteriogenesis is triggered by changes in local hemodynamic conditions and subsequent activation of inflammatory pathways. We previously showed that expression of kininogen, a precursor of the vasoactive kinin peptides, was selectively expressed in growing collaterals of the rat brain. 2 Here we investigated the role of kinin signaling in bradykinin receptor-deficient mice for collateral growth and evaluated whether stimulation with bradykinin receptor antagonists/agonists may modulate arteriogenesis in mice and rats. Our data suggest that the kinin-receptor signaling pathway may act as a molecular link between changes in hemodynamic forces (artery occlusion) and the activation of inflammatory pathways, including attraction of bone marrow Original Methods and Results:

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