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

Myeloid-specific Gpnmb deletion worsened cardiac dysfunction, hypertrophy, fibrosis, and capillary rarefaction after transverse aortic constriction (TAC) in mice.

• Myeloid-specific Gpnmb knockout and control mice were subjected to transverse aortic constriction.
• Cardiac function, remodeling, and capillary density were assessed.
• Knockout mice showed exacerbated cardiac dysfunction, hypertrophy, fibrosis, and capillary rarefaction compared with controls.

Single-cell RNA sequencing of myeloid Gpnmb knockout hearts showed a reduced capillary endothelial cell population and transcriptomic changes indicating endothelial dysfunction and metabolic reprogramming.

• Single-cell RNA sequencing was performed to identify transcriptomic changes after TAC.
• Pathway enrichment was indicative of endothelial dysfunction and metabolic reprogramming in knockout hearts.
• The reduced capillary endothelial cell population is consistent with the observed capillary rarefaction.

Recombinant GPNMB directly promoted proliferation, migration, and tube formation of human endothelial cells.

• In vitro assays used human endothelial cells treated with recombinant GPNMB.
• The proangiogenic effects were observed independently of VEGF signaling.

GPNMB promotes angiogenesis by activating the mTOR pathway in a CD44-dependent manner, independent of VEGF.

• In vitro mechanistic studies dissected the underlying signaling pathways.
• The authors state that the axis is 'probably' CD44/mTOR, supported by in vitro mechanistic studies rather than in vivo proof.

Cardiac-specific Gpnmb overexpression via AAV9 rescued angiogenesis, improved cardiac function, and attenuated pathological remodeling after TAC.

• Therapeutic potential was evaluated using AAV9 vectors for Gpnmb overexpression.
• Overexpression restored angiogenesis and reduced pathological remodeling after pressure overload.

The authors conclude macrophage-derived GPNMB is a critical regulator of cardiac adaptation to pressure overload and a potential therapeutic target for heart failure with microvascular rarefaction.

• GPNMB promotes a VEGF-independent angiogenic program, offering an alternative to VEGF-based therapies, which have limitations.
• The conclusion is supported by loss-of-function in mice, gain-of-function with AAV9, and in vitro mechanistic work.