The role of Na+/H+ exchange and growth factors in pulmonary artery smooth muscle cell proliferation

Chronic hypoxia produces pulmonary hypertension, in part because of hypertrophy and hyperplasia of pulmonary artery smooth muscle cells (PA SMC). Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) have been shown to stimulate SMC proliferation and may be involved in these vascular changes. Both factors cause a rise in intracellular pH (pH(i)) in systemic vascular SMC through stimulation of the Na+/H+ exchanger, an event that has been thought to be permissive, allowing cell proliferation in response to the growth factor. The present studies examined the possibility that the activation of Na+/H+ exchange is involved in the PA SMC mitogenic response to these growth factors. Na+/H+ exchange activity was assessed by monitoring pH(i) in cultured cells using the pH-sensitive dye, 2'7'-bis(carboxyethyl)-5(6)-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). PDGF (60 ng/ml) exposure led to a marked activation of Na+/H+ exchange, evidenced by a rise in pH(i) (mean +/- SEM) of 0.20 +/- 0.03 pH units (n = 5, P < 0.05). EGF (60 ng/ml) exposure produced a rise in pH(i) of 0.27 +/- 0.03 pH units (n = 5, P < 0.05). Dimethyl amiloride (DMA, 50 mu M), a competitive inhibitor of Na+/H+ exchange, blocked the pH response to PDGF and EGF. PA SMC showed a proliferative response when exposed to PDGF and EGF which was attenuated by 50 mu M DMA (n = 6). Thus, activation of the Na+/H+ exchanger may be important in pulmonary cell signaling in response to growth factors as it has been found to be in systemic vessels.