Epidermal growth factor receptor (EGFR) mediates vascular responses to high altitude long‐term hypoxia

High‐altitude long‐term hypoxia (LTH) in the fetus may result in pulmonary vascular smooth muscle cell (PVSMC) proliferation and vascular remodeling. The role of EGFR in this is unclear. Objective: To determine if EGFR is involved in hypoxia‐induced PVSMC proliferation or in pulmonary vascular remodeling in the LTH fetus. Pregnant ewes were at 3,820m altitude from ~35–140 days gestation. Ovine fetuses were delivered near term. Sea‐level controls were used. Morphometric analyses and immunohistochemistry were done on fetal lung sections. Western blot analyses were done on protein isolated from pulmonary vessels. Control fetal ovine PVSMC proliferation under chronic hypoxia (2% O 2 ) was measured with a cell‐counting kit and by thymidine incorporation. EGFR expression was upregulated in LTH fetal ovine pulmonary vessels. This was specific to PVSMC in the medial wall by immunohistochemistry. These pulmonary vessels also exhibited medial wall thickening and distal muscularization. By inhibiting EGFR with 250μM AG1478, a specific EGFR protein tyrosine kinase inhibitor or by transfection of a dominant negative EGFR construct, control PVSMC proliferation in 24 h hypoxia was attenuated. Our results show that EGFR plays a significant role in fetal ovine pulmonary vascular remodeling following LTH. We speculate that inhibition of EGFR signaling may reverse hypoxia‐induced pulmonary vascular remodeling. Grants HL077819, HL075187