The CXCL12γ/ACKR3 Axis Is a Critical Determinant of Myocardial Angiogenesis and Functional Recovery After Infarction.

Following myocardial infarction, the CXCL12γ-heparan sulfate-ACKR3 axis emerges as a critical, localized signaling mechanism for cardiac repair. Unlike the α isoform, CXCL12γ exhibits superior affinity for ACKR3. Although genetic disruption of CXCL12γ-heparan sulfate binding impairs postischemic angiogenesis and function, its overexpression rescues these deficits. Mechanistically, cardiomyocyte-specific ACKR3 is vital for the regulation of cardiac function, whereas fibroblast-specific ACKR3 orchestrates a proangiogenic paracrine program. This study identifies CXCL12γ as a noncanonical ligand that activates fibroblast-mediated microvascular expansion via ACKR3, offering a novel therapeutic target to enhance myocardial recovery and preserve cardiac performance.