Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation

Abstract

Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

“…While the Warburg effect focuses on glycolysis, the PPP, which yields reductive NADPH and ribose-5-phosphate for nucleotide synthesis, is often augmented in parallel with glycolysis. PPP flux is upregulated in pulmonary vascular cells in multiple PH models (16,(32)(33)(34). Increased activity of the rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) was observed in pulmonary artery smooth muscle cells (PASMCs) of chronically hypoxic rats (32), suggesting that G6PD deficiency may protect against PH development (35).…”

Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis

“…On the other hand, extensive metabolic reprogramming resulting from overadaptation to hypoxia, exposure to inflammatory mediators, or diseasespecific differences in metabolic regulation may also lead to aberrant cellular function. In cancer and pulmonary hypertension, a shift from OXPHOS to the use of glycolysis and glutaminolysis as energy sources leads to the production of intermediates for synthesis of lipids, amino acids, nucleotides, and antioxidants required for maintaining proliferation and survival (104,105). We have demonstrated mitochondrial dysfunction and impaired OXPHOS in ASMCs from patients with COPD (8).…”

Fetal hemodymanic effects on ductus arteriosus development and influences on postnatal management in infants with ductal-dependent pulmonary blood flow

“…In the case of pulmonary atresia, the DA carries less than 10% of CVO and the balance of the effects of decreased CVO of higher oxygenation is not known but is thought to result in abnormalities of the pulmonary vascular bed. 3 As increased pulmonary blood flow results in early smooth muscle hyperproliferation, 13 other abnormalities of smooth muscle development are likely in such aberrations as noted above with decreased flow or increased oxygenation. Pulmonary blood flow with higher oxygenation than usual may decrease pulmonary vascular resistance during vascular development, which has been posited as decreasing the stimulus for growth of medial smooth muscle with subsequent attenuated reaction to vasostimulation.…”