Myeloid ALX/FPR2 regulates vascularization following tissue injury

Ischemic injury initiates a sterile inflammatory response that ultimately participates in the repair and recovery of tissue perfusion. Macrophages are required for perfusion recovery during ischemia, in part because they produce growth factors that aid in vascular remodeling. The input signals governing this pro-revascularization phenotype remain of interest. Here we found that hindlimb ische- mia increases levels of resolvin D1 (RvD1), an inflammation - resolving lipid mediator that targets macrophages via its receptor, ALX/FPR2. Exogenous RvD1 enhances perfusion recovery during ischemia, and mice deficient in Alx/Fpr2 have an endogenous de- fect in this process. Mechanistically, RNA sequencing revealed that RvD1 induces a transcriptional program in macrophages character- istic of a pro-revascularization phenotype. Vascularization of ische- mic skeletal muscle, as well as cutaneous wounds, is impaired in mice with myeloid -specific deficiency of Alx/Fpr2 , and this is asso- ciated with altered expression of pro-revascularization genes in skeletal muscle and macrophages isolated from skeletal muscle. Collectively, these results uncover a role of ALX/FPR2 in revascu- larization that may be amenable to therapeutic targeting in dis- eases associated with altered tissue perfusion and repair.