Abstract Body: Cardiac hypertrophy represents an adaptive response to pressure overload and involves macrophage-mediated angiogenesis. However, the morphological basis of macrophage–endothelial cell interactions and the molecular mechanisms governing this response remain poorly understood. Using a tissue-clearing method developed in our laboratory, we identified a previously unrecognized pro-angiogenic microenvironment localized 100–200 μm beneath the epicardium in mice one week after transverse aortic constriction (TAC). This subepicardial region was characterized by the marked accumulation of myeloid cells, which was closely associated with enhanced vascular proliferation and increased structural complexity. Macrophage depletion blunted the angiogenic response and exacerbated cardiac dysfunction following TAC. Layer-resolved spatial transcriptomic analysis revealed enhanced TGF-β responsiveness in macrophages, with angiogenin identified as a key downstream effector. Consistently, myeloid-specific deletion of TGF-β receptor 2 suppressed angiogenic remodeling and impaired cardiac function. Notably, administration of angiogenin restored angiogenesis and preserved contractile performance in macrophage-depleted hearts after TAC. Collectively, these findings define a spatially restricted, subepicardial macrophage–angiogenin–dependent microenvironment that orchestrates adaptive angiogenesis during the early phase of pressure overload, highlighting angiogenin as a potential therapeutic target for acute heart failure.