Cyclic mechanical stretch induces VEGF and FGF-2  expression in pulmonary vascular smooth muscle cells

Quinn, Tim; Schlueter, Marielle; Soifer, Scott J.; Gutiérrez, Jorge

doi:10.1152/ajplung.00044.2001

Cited by 96 publications

(74 citation statements)

References 54 publications

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“…The increase in FGF-2 promoter activity in PASMC after 24 h of stretch is in agreement with a previous study demonstrating an 80% increase in FGF-2 mRNA in ovine PASMC exposed to 24 h of cyclic stretch (16). Our data further add to the existing knowledge of FGF-2 expression in SMC by demonstrating a role for shear stress in its regulation.…”

Section: Discussionsupporting

confidence: 92%

“…Plates were placed on a loading station and stretched by applying an oscillatory vacuum to the underside of the membranes. Cells were stretched at a frequency of 1 Hz with 20% amplitude for 8 -24 h in accordance with a previous study (16).…”

Section: Methodsmentioning

confidence: 99%

“…EC are also subjected to shear stress due to blood flow, and fluid dynamic models of intact blood vessels suggest that SMC also experience shear stress as a result of interstitial flow (15). Cyclic stretch increased FGF-2 mRNA in PASMC (16) and shear stress increased the release of FGF-2 from aortic SMC (17) and aortic EC (18). Since these biomechanical forces are increased in shunt pulmonary arteries due to elevated pulmonary blood flow, we hypothesized that similar to monocrotaline-induced and adult pulmonary hypertension, increased FGF-2 signaling may be associated with pulmonary vascular remodeling in shunt lambs.…”

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confidence: 99%

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

et al. 2007

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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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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2007

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“…In cardiac myocytes, a 1.8-fold increase in VEGF mRNA that peaked at 2 h was found [55]. In a pulmonary cell culture model [41], stretch increased VEGF mRNA expression (1.8-fold). In contrast, intermittent hydrostatic pressure decreased VEGF expression in cultures of rat Achilles tendon fibroblasts [33].…”

Section: Discussionmentioning

confidence: 91%

Cyclic strain influences the expression of the vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF‐1α) in tendon fibroblasts

Petersen

Varoga

Zantop

et al. 2004

Journal Orthopaedic Research

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Neovascularization is involved in beneficial and detrimental processes of tendon pathology. We investigated the influence of repetitive motion on the expression of the most important angiogenic factor, the vascular endothelial growth factor (VEGF) in the 3T3 NIH fibroblast cell line and in cultures of rat Achilles tendon fibroblasts. Monolayers of subconfluently grown cells were stretched in rectangular silicone dishes with cyclic uniaxial movement. Strain was applied over 24 h varying the frequency (0.5–1 Hz). Fibroblasts (3T3 fibroblasts and rat Achilles tendon cultures) cultivated without the application of cyclic strain released measurable VEGF amounts into their culture supernatants. Cyclic stretching of the cells with a frequency of 1 Hz resulted in an increased expression of VEGF. A low frequency (0.5 Hz) reduced VEGF expression to control levels. RT PCR revealed VEGF 121 and VEGF 165 as the only splice forms that were induced by cyclic stretching. Western blot experiments could further show that cyclic stretching induced activation of the transcription factor HIF‐1α. These results demonstrate that mechanical factors are involved in the regulation of VEGF expression in tendon tissue. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

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“…The most likely mechanism that could be implicated in both eNOS and VEGF upregulation is circumferential vascular stretch, which indeed occurs in the intestinal microcirculation after an increase in venous pressure in the mesenteric system (9) and previously has been shown to activate VEGF (10,26,28,30,34) and eNOS (24). Moreover, the preferential distribution of VEGF expression in the mucosal vasculature may be due to a greater percentage change in mesenteric venous pressure being transmitted into the mucosal layer than into the muscularis (9).…”

Section: Discussionmentioning

confidence: 99%

Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state

Abraldes

Iwakiri²,

Loureiro-Silva³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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135

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increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 290: G980 -G987, 2006; doi:10.1152/ajpgi.00336.2005.-Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation. cirrhosis; vasodilation A HALLMARK of portal hypertension (PHT) syndrome is a hyperdynamic circulatory state, characterized by splanchnic and peripheral vasodilation, increased plasma volume, and increased cardiac output (CO) (18). This hyperkinetic syndrome is the result of an increased production of vasodilators, mainly nitric oxide (NO), in the peripheral and splanchnic circulation (for a review, see Ref. 42). A number of mechanisms, including shear stress (20), bacterial translocation (39, 40), or portosystemic shunting (PSS) (1, 2), have been proposed to explain the upregulation of endothelial NO synthase (eNOS), the isoform that accounts for the increased NO production in PHT. However, it has been demonstrated that eNOS activation occurs before any of these mechanisms is present (22,43), and the signals that initially trigger NO hyperproduction in PHT are still poorly understood.The partial portal vein ligation (PVL) model has been shown to reproduce the systemic and hemodynamic abnormalities in PHT (37). Furthermore, its highly predictable chronobiology has allowed the elucidation of the sequences of events leading to hyperdynamic circulation (8,33). Thus this model also offers the opportunity to sequentially evaluate the molecular mechanisms leading to the hemodynamic abnormalities observed in hyperdynamic circulation. In that regard, a recent study from our laboratory suggested that, in the commonly used PVL model, in which portal vein stenosis is calibrated over a 20-gauge needle (37), the myogenic response that occurs in the s...

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Cyclic mechanical stretch induces VEGF and FGF-2 expression in pulmonary vascular smooth muscle cells

Cited by 96 publications

References 54 publications

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

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

Cyclic strain influences the expression of the vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF‐1α) in tendon fibroblasts

Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state

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