Polyamines and Epidermal Growth Factor in Monocrotaline-induced Pulmonary Hypertension

Abstract

Multiple lines of evidence suggest that the polyamines, a family of low-molecular-weight organic cations with documented regulatory note in cell growth and differentiation, are involved with hyperplastic and hypertrophic responses of lung cells underlying hypertensive pulmonary vascular disease. Little is known, however, of the factor(s) initiating polyamine synthesis in pulmonary hypertension. This study tested the key aspects of the hypothesis that augmented polyamine synthesis, and attendent vascular structural alterations in monocrotaline (MCT)-treated rats can be ascribed to elaboration of an epidermal growth factor (EGF)-like mitogen. In lungs of rats treated 4 days previously with 60 mg/kg, EGF-like immunoreactivity was detected diffusely throughout perivascular regions. Intravenous administration of human recombinant EGF (125 pg/h) to rats for 1 wk was associated with medial thickening in pulmonary arteries between 100 and 200 microns in diameter, significant increases in lung polyamine contents, and a moderate elevation in mean pulmonary arterial pressure. These observations indicate that EGF can be detected in the lungs of MCT-treated rats and that exogenous EGF mimics some of the action of MCT on the rat lung. It is thus reasonable to speculate that an EGF-like mitogen may participate in the response to MCT in part through a polyamine-dependent mechanism.

Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease

“…Several growth factors, including EGF, PDGF, and TGF-β1, participate in the process of pulmonary vascular remodeling in patients with pulmonary hypertension and in animal models (2,(5)(6)(7)(8). For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8-10).…”

“…For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8)(9)(10). Blockade of EGFR results in reductions in pulmonary pressure, right ventricular hypertrophy, and distal arterial muscularization in MCT-induced pulmonary hypertension (11).…”

“…Pulmonary vascular remodeling is an important common pathological feature of all categories of pulmonary hypertension. Accumulation of extracellular matrix, including collagen, and vascular smooth muscle cell proliferation and hypertrophy contribute to medial hypertrophy and muscularization, leading to obliteration of precapillary pulmonary arteries and sustained elevation of pulmonary arterial pressure (3, 4).Several growth factors, including EGF, PDGF, and TGF-β1, participate in the process of pulmonary vascular remodeling in patients with pulmonary hypertension and in animal models (2,(5)(6)(7)(8). For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8-10).…”

Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline.

“…There are two widely used small animal models of chronic pulmonary hypertension: exposure to chronic hypoxia (1, 2) and the "inflammatory" model of pulmonary hypertension in rats injected with the alkaloid monocrotaline (MCT) (3)(4)(5)(6)(7)(8)(9)(10). We have recently reported that chronic administration of platelet-activating factor (PAF) receptor antagonists prevents the development of pulmonary hypertension in both models (2,6,7), suggesting that the ether lipid PAF directly or indirectly is involved in the vascular remodeling and pulmonary hypertension in these animal models.…”

Hipertensão arterial pulmonar: fisiopatologia, aspectos genéticos e resposta ao uso crônico do sildenafil

“…Nitric oxide (NO), an endothelium-derived vasodilator, has also an antiproliferative action over vascular smooth musculature 14 , possibly connected to intracellular cyclic GMP generation. In fact, it has been considered that phosphodiesterase 5 enzyme (which degrades cyclic GMP) inhibitors could act on hypoxia-induced pulmonary vascular remodeling 15 .…”