Fibroblast Growth Factor-2 Expression Is Altered in Lambs With Increased Pulmonary Blood Flow and Pulmonary Hypertension

Abstract

A lamb model of pulmonary hypertension, developed by inserting an aortopulmonary vascular graft (shunt), displays vascular remodeling and increased pulmonary blood flow characteristic of children with congenital heart disease. The purpose of this study was to determine whether expression of fibroblast growth factor-2 (FGF-2), a smooth muscle cell mitogen, is altered in shunt lambs. FGF-2 mRNA and protein levels were increased in lung tissue extracts from shunt lambs at 4 wk of age relative to age-matched controls (p Ͻ 0.05). FGF-2 protein levels were also increased in the pulmonary arteries and serum of shunt lambs (p Ͻ 0.05). Pulmonary arterial smooth muscle cells (PASMC) and endothelial cells (PAEC) were isolated from 4 wk-old lambs and subjected to cyclic stretch and laminar shear stress to mimic increased pulmonary blood flow. Stretch and shear increased FGF-2 promoter activity, and intracellular and extracellular FGF-2 protein levels in both cell types (p Ͻ 0.05). Exogenous FGF-2 stimulated PASMC proliferation at levels detected in the extracellular medium of sheared cells (p Ͻ 0.05). Elevated FGF-2 signaling by PASMC and PAEC exposed to increased pulmonary blood flow may play a role in the pulmonary vascular remodeling associated with the shunt model of pulmonary hypertension secondary to congenital heart disease. (Pediatr Res 61: 32-36, 2007) C HD with increased pulmonary blood flow is often associated with the development of pulmonary hypertension (1). After birth, as pulmonary vascular resistance normally decreases, the presence of a systemic to pulmonary communication generates an increase in pulmonary blood flow. This abnormal postnatal hemodynamic state results in progressive structural and functional abnormalities of the pulmonary vascular bed (2,3). Our animal model of pulmonary hypertension, developed by inserting an aortopulmonary vascular graft in the late-gestational fetal lamb (4 -6), may help elucidate the mechanisms involved. Postnatally, these shunt lambs have increased pulmonary blood flow and pressure (4). In addition, they display vascular remodeling typical of pulmonary hypertension secondary to CHD, characterized by increased medial wall thickness of the small pulmonary arteries and abnormal extension of muscle to peripheral pulmonary arteries (1,4,7).Recent studies have demonstrated that shunt lambs display abnormal signaling by several growth factors mitogenic for vascular smooth muscle, including ET-1 (6), transforming growth factor ␤-1 (TGF ␤-1) (8), and vascular endothelial growth factor (VEGF) (9). Another potential contributor to vascular remodeling is FGF-2. FGF-2 displays mitogenic effects in the early proliferation of SMC (10,11) and in neointimal thickening (12) following vascular injury. Furthermore, a progressive increase in FGF-2 protein within the smooth muscle layer of pulmonary arteries was demonstrated in a rat model of monocrotaline-induced pulmonary hypertension (13). In addition, elevated FGF-2 protein levels were detected in the urine and plasma of patie...

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