Changes in Fetal Lung Distension Alter Expression of Vascular Endothelial Growth Factor and Its Isoforms in Developing Rat Lung

Hara, Akihiko; Chapin, Cheryl J.; Ertsey, Robert; Kitterman, Joseph A.

doi:10.1203/01.pdr.0000163614.20031.c5

Cited by 44 publications

(49 citation statements)

References 65 publications

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“…Hara et al had previously shown that antenatal tracheal occlusion (another therapeutic strategy to promote lung growth in CDH 1 ) increases VEGF-A protein expression and suggested that VEGF-A mediates previously described changes in lung vascular and parenchymal development caused by tracheal occlusion. 43 Similar data were reported by Cloutier et al in mice. 50 The mechanism by which sildenafil increases lung eNOS and VEGF expression remains speculative.…”

Section: Discussionsupporting

confidence: 83%

“…[43][44][45] More interestingly, NO and VEGF promote airway branching in normal and CDH lung explants, 36,46,47 and in vivo, inhaled NO prolongs survival in CDH rat pups and this effect could be enhanced with prenatal glucorticoids. 48,49 Here, we investigated whether administration of antenatal sildenafil could have a beneficial effect on the hypoplastic nitrofen lung in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

et al. 2011

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Background-Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. Methods and Results-Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. Conclusions-Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/ morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies. (Circulation. 2011;123:2120-2131.)

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

et al. 2011

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“…Recent studies indicate that VEGF is essential for normal pulmonary parenchymal development (26). In addition, VEGF is expressed in distal lung epithelial cells and its mRNA and protein levels are increased by mechanical forces (27). These studies support a Probe set ID numbers refer to rat E230A GeneChips from Affymetrix.…”

Section: Discussionmentioning

confidence: 54%

DNA Microarray Reveals Novel Genes Induced by Mechanical Forces in Fetal Lung Type II Epithelial Cells

et al. 2006

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Mechanical forces are essential for normal fetal lung development. However, the cellular and molecular mechanisms regulating this process are still poorly defined. In this study, we used oligonucleotide microarrays to investigate gene expression in cultured embryonic d 19 rat fetal lung type II epithelial cells exposed to a level of mechanical strain similar to the developing lung. Significance Analysis of Microarrays (SAM) identified 92 genes differentially expressed by strain. Interestingly, several members of the solute carrier family of amino acid transporter (Slc7a1, Slc7a3, Slc6a9, and tumor-associated protein 1) genes involved in amino acid synthesis (Phgdh, Psat1, Psph, Cars, and Asns), as well as the amiloride-sensitive epithelial sodium channel gene (Scnn1a) were up-regulated by the application of force. These results were confirmed by quantitative real-time PCR (qRT-PCR). Thus, this study identifies genes induced by strain that may be important for amino acid signaling pathways and protein synthesis in fetal type II cells. In addition, these data suggest that mechanical forces may contribute to facilitate lung fluid reabsorption in preparation for birth. Taken together, the present investigation provides further insights into how mechanical forces may modulate fetal lung development. N ormal lung growth and development during fetal life are critical for extrauterine survival. Premature infants are often born before sufficient lung maturation has occurred, and, as a result, they experience a high rate of long-term pulmonary complications such as bronchopulmonary dysplasia. Understanding the mechanisms of prenatal lung growth and development is a crucial step for the design of preventive and therapeutic strategies.Mechanical forces generated in utero by repetitive breathing movements and by fluid distension are essential to mammalian lung development (1-3). Previous in vitro experiments have demonstrated that application of force to cultured type II epithelial cells induces cell proliferation (4) and differentiation (5). Other studies have begun to identify mechanoreceptors and cell signaling pathways mediating fetal lung growth and maturation (4 -8). However, the precise molecular and cellular mechanisms by which lung cells sense mechanical stimuli to influence lung development are still poorly defined.DNA microarray technology provides a powerful tool for rapid, comprehensive, and quantitative analysis of gene expression profile. This technique has been previously used to assess changes in gene expression in endothelial cells (9), bladder smooth muscle cells (10), and human pulmonary A549 (11) and H441 (12) epithelial cells exposed to mechanical strain.Therefore, the goal of the present study was to identify genes differentially expressed by mechanical stress of fetal type II epithelial cells. We used an in vitro model system in which embryonic d (E) 19 type II cells are exposed to mechanical forces similar to that observed in the developing lung. These studies revealed that mechanical force...

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“…For example, VEGFs might demonstrate a different profile and role in acute PH states due to impaired pulmonary vasodilatation, such as PPHN, compared with chronic PH states involving structural changes in pulmonary vasculature, such as in severe CDH or idiopathic PH. Another important consideration is that the severity of pulmonary vascular disease, in any disease state, may not be related to absolute levels of a single growth factor alone but instead to disease-specific variations in relative proportions of VEGF isoforms and receptor subtypes (14).…”

Section: Discussionmentioning

confidence: 99%

Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia

Patel

Moenkemeyer

Germano

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Changes in Fetal Lung Distension Alter Expression of Vascular Endothelial Growth Factor and Its Isoforms in Developing Rat Lung

Cited by 44 publications

References 65 publications

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

DNA Microarray Reveals Novel Genes Induced by Mechanical Forces in Fetal Lung Type II Epithelial Cells

Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia

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