Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by high blood pressure in the pulmonary circulation driven by pathological remodeling of distal pulmonary arteries, leading typically to death by right ventricular failure. Available treatments improve physical activity and slow disease progression, but they act primarily as vasodilators and have limited effects on the biological cause of the disease—the uncontrolled proliferation of vascular endothelial and smooth muscle cells. Imbalanced signaling by the transforming growth factor-β (TGF-β) superfamily contributes extensively to dysregulated vascular cell proliferation in PAH, with overactive pro-proliferative SMAD2/3 signaling occurring alongside deficient anti-proliferative SMAD1/5/8 signaling. We review the TGF-β superfamily mechanisms underlying PAH pathogenesis, superfamily interactions with inflammation and mechanobiological forces, and therapeutic strategies under development that aim to restore SMAD signaling balance in the diseased pulmonary arterial vessels. These strategies could potentially reverse pulmonary arterial remodeling in PAH by targeting causative mechanisms and therefore hold significant promise for the PAH patient population.
Highlights
We review the transforming growth factor-β (TGF-β) superfamily mechanisms underlying Pulmonary arterial hypertension (PAH) pathogenesis, superfamily interactions with inflammation and mechanobiological forces, and therapeutic strategies under development that aim to restore SMAD signaling balance in the diseased pulmonary arterial vessels
In PAH, recent evidence indicates a signaling imbalance between the two principal canonical pathways, with underactive SMAD1/5/8 signaling occurring alongside overactive SMAD2/3 signaling in pulmonary arterial Endothelial cells (ECs) and SMCs [13]. We describe how this SMAD signaling imbalance influences the exuberant cell proliferation underlying vascular remodeling and describe therapeutic approaches for either attenuating excessive SMAD2/3 signaling or restoring deficient SMAD1/5/8 signaling in diseased pulmonary vasculature [14,15,16,17,18,19,20]
The TGF-β superfamily of ligands and receptors plays a critical role in the development and severity of PAH
Summary
Mice with Bmpr ablated from monocyte-lineage macrophages exhibited muscularized pulmonary arteries and increased right ventricular systolic pressure after Sugen-hypoxia treatment while depletion of macrophages with clodronate reversed these parameters [43] Together, these studies suggest that BMPRII-mediated signaling within the pulmonary vasculature normally protects against inflammation-induced vascular remodeling. Steady-state laminar flow, the pattern typical of healthy vasculature, promotes EC quiescence by facilitating activation of the BMPRII-SMAD1/5/8 axis (Figure 1) [98] This signaling pathway prevents cell cycle progression by ECs and contributes to the stabilization of EC cellular junctions, preventing vascular remodeling processes.
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