Figure 1.

Expansion of Biomass as a Driver of PAH Pathobiology

Pulmonary arterial hypertension (PAH) is defined by fibroproliferative remodeling and plexiform growth, resulting from fibrosis and expansion of extracellular matrix, proliferation of endothelial cells and mesenchymal cells, and infiltration of immune and inflammatory cells. This massive increase in the cellular and extracellular material that comprises the vessel wall and occupies the vessel lumen represents the collective pathological biomass. (Circle inset) If expansion of cellular biomass is reduced to the atomic level, critical elemental components including the carbon and nitrogen backbone of biomass can be sourced from a variety of substrates and interconnected metabolic pathways. Although macromolecular building blocks can be imported into cells to directly supply anabolic production of biomass, including key components such as DNA (nucleotides), collagen (amino acids), cytoskeleton (amino acids), and lipid (fatty acids), there are also multiple paths by which atoms can flux from one building block type to another because the catabolic breakdown of molecules can in turn supply substrate for alternative biosynthetic pathways. The tricarboxylic acid (TCA) cycle represents a useful example of this concept. The TCA cycle is supplied by catabolism of amino acids, glucose, and fatty acids. Aside from its central role in energy production, it also serves as a hub in the trafficking of substrate to diverse biosynthetic pathways, including protein synthesis and de novo nucleotide synthesis. In this manner, the new DNA synthesized during cell division may contain atoms derived from nucleotides, fatty acids, amino acids, and glucose.