Macrophage‐Derived Glycoprotein Nonmetastatic Melanoma Protein B Attenuates Cardiac Dysfunction by Promoting Vascular Endothelial Growth Factor‐Independent Angiogenesis

Background Pressure overload‐induced heart failure involves maladaptive cardiac remodeling and inadequate angiogenesis. The limitations of VEGF (vascular endothelial growth factor)‐based therapies underscore the need to identify alternative angiogenic pathways. GPNMB (glycoprotein nonmetastatic melanoma protein B) is a macrophage‐secreted protein implicated in tissue repair, but its role in pressure overload‐induced cardiac remodeling and its potential to modulate angiogenesis remain unknown. Methods Myeloid‐specific Gpnmb knockout and control mice were subjected to transverse aortic constriction. Cardiac function, remodeling, and capillary density were assessed. Single‐cell RNA sequencing was performed to identify transcriptomic changes. In vitro, human endothelial cells were treated with recombinant GPNMB to assess proliferation, migration, and tube formation, and to dissect the underlying signaling pathways. The therapeutic potential of Gpnmb overexpression was evaluated using AAV9 vectors. Results Myeloid Gpnmb deletion exacerbated transverse aortic constriction‐induced cardiac dysfunction, hypertrophy, fibrosis, and capillary rarefaction. Single‐cell sequencing revealed a reduced capillary endothelial cell population and pathway enrichment indicative of endothelial dysfunction and metabolic reprogramming in myeloid‐specific Gpnmb knockout hearts. Mechanistically, GPNMB directly promoted endothelial cell proliferation, migration, and tube formation by activating the mTOR (mechanistic target of rapamycin) pathway in a CD44‐dependent manner, independently of VEGF signaling. Cardiac‐specific Gpnmb overexpression rescued angiogenesis, improved cardiac function, and attenuated pathological remodeling after transverse aortic constriction. Conclusions Macrophage‐derived GPNMB is a critical regulator of cardiac adaptation to pressure overload. It promotes a VEGF‐independent angiogenic program probably via the CD44/mTOR axis, as supported by in vitro mechanistic studies. GPNMB represents a promising therapeutic target for heart failure characterized by microvascular rarefaction.