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

Abstract

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 (pHi) 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 pHi in cultured cells using the pH-sensitive dye, 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). PDGF (60 ng/ml) exposure led to a marked activation of Na+/H+ exchange, evidenced by a rise in pHi (mean +/- SEM) of 0.20 +/- 0.03 pH units (n = 5, P < 0.05). EGF (60 ng/ml) exposure produced a rise in pHi of 0.27 +/- 0.03 pH units (n = 5, P < 0.05). Dimethyl amiloride (DMA, 50 microM), 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 microM 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.

Silencing of Sodium–Hydrogen Exchanger 1 Attenuates the Proliferation, Hypertrophy, and Migration of Pulmonary Artery Smooth Muscle Cells via E2F1

“…We previously reported on the inhibitory effect of reduced NHE activity in the proliferation of PASMCs (6) and on chronic hypoxia-induced pulmonary hypertension and vascular remodeling (7). Increased expression of the NHE1 gene was evident in animals with hypoxia-induced pulmonary hypertension and vascular remodeling (6)(7)(8)(9)(10). Moreover, we recently found that deficiency of the NHE1 gene prevented hypoxia-induced pulmonary hypertension and vascular remodeling in mice (11), accompanied by a significantly reduced proliferation of PASMCs and decreased medial wall thickness of the pulmonary arteries.…”

The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway

“…It has been demonstrated that dimethyl amiloride, a potent and specific inhibitor of the Na ϩ /H ϩ transporter, can inhibit pulmonary artery smooth muscle cell (PASMC) proliferation in vitro and chronic-hypoxia-induced pulmonary hypertension in rats (35,36). Unlike DMA, phenamil, benzamil, and amiloride are potent blockers of Na ϩ channels, including epithelial sodium channels (ENaCs) and acid-sensing ion channels (ASICs).…”

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

“…PDGF has been shown to stimulate rat 108 and bovine 55 PASMC proliferation, as well as human PASMC proliferation and migration, 109 through pathways involving upregulated capacitative Ca 2+ entry 108,110 and increased NHE activity. 55 Similarly, the peptide ET-1, a potent endothelial-derived vasoconstricting agent released primarily by endothelial cells, is upregulated in multiple forms of PH, including hypoxia-induced PH, and ET-1 receptor inhibitors have been successful in preventing and partially reversing hypoxic PH in animal models. [111][112][113] Acute incubation with ET-1 increased NHE activity in a dose-dependent fashion in normoxic rat PASMCs.…”

“…Initially, DMA was found to inhibit growth factor-induced PASMC proliferation in vitro. 55 In vivo, it was subsequently determined that both DMA and EIPA, when given during a hypoxic exposure of 10% O 2 for 14 days, inhibited the development of PH in rats. 99 The attenuated development of PH with DMA and EIPA was achieved through decreased hypoxia-induced pulmonary vascular remodeling, as drug-treated animals showed decreased wall thickness of intra-acinous vessels, compared to untreated hypoxic controls.…”