Extracellular signal-regulated kinases 1 and 2 contribute to proliferation of pulmonary arterial smooth muscle cells

Chronic hypoxia (CH) leads to the development of pulmonary hypertension, and pulmonary vascular remodeling contributes to disease pathogenesis. Although the mechanisms underlying CH-induced pulmonary vascular remodeling are not fully understood, they involve proliferation of pulmonary arterial smooth muscle cells (PASMCs). Previous studies suggest that extracellular signal-regulated kinases 1 and 2 (ERK1/2) may be important drivers of PASMC proliferation. Therefore, we hypothesized that CH activates extracellular signal-regulated kinases 1 and 2 to facilitate PASMC proliferation. To test our hypothesis, we performed immunoblotting in both pulmonary arteries and primary cultures of PASMCs from normoxic and CH (1 wk, 0.5 atm) rats to assess 1) ERK1/2 phosphorylation status (Thr202/Tyr204) as a measure of ERK1/2 activation, and 2) PCNA abundance as a marker of cell proliferation. To evaluate the role of ERK1/2 in PASMC proliferation, we treated primary cultures with the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor, U0126 (10 μM). Hypoxia increased ERK1/2 phosphorylation (phosphorylated ERK1/2 to total ERK1/2) and PCNA abundance (PCNA to β-actin) in pulmonary arterial homogenates, with a significant positive correlation (r=0.75; p< 0.05), suggesting ERK1/2 activation is associated with CH-induced PAMSC proliferation. Similar changes were observed in primary cultures of PASMCs from these groups. Treatment with U0126 abolished hypoxia-induced ERK1/2 phosphorylation in primary PASMC. U0126 significantly reduced PCNA abundance in both cell groups, with levels remaining statistically higher in the hypoxic group than in the normoxic group. In conclusion, these results suggest that 1) hypoxia increases proliferation of PASMCs; 2) ERK1/2 is activated by hypoxia in PASMCs; and 3) ERK1/2 plays a key role in driving PASMC proliferation, but it is not the only contributing pathway under hypoxic conditions. This work is supported by NIH grant R01 HL169945 (to T.C. Resta). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.