Knockout of Insulin-Like Growth Factor-1 Receptor Impairs Distal Lung Morphogenesis

Epaud, Ralph; Aubey, Flore; Xu, Jie; Chaker, Zayna; Clemessy, Maud; Dautin, Alexandre; Ahamed, K.F.H. Nazeer; Bonora, M.; Hoyeau, Nadia; Fléjou, Jean‐François; Mailleux, Arnaud; Clément, Annick; Henrion‐Caude, Alexandra; Holzenberger, Martin

doi:10.1371/journal.pone.0048071

Cited by 64 publications

(61 citation statements)

References 30 publications

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“…IGF-1/IGF-1R has been shown to be required for normal lung development, pulmonary vascularization, and proper alveolarization (8,15,16). In our study, we observed that lung IGF-1 levels in mice increased significantly after birth before returning to baseline at around 2 weeks of age, coinciding with the period of postnatal alveolarization in mice and consistent with an important function of IGF-1 in lung development after birth ( Figure 1A).…”

Section: Discussionsupporting

confidence: 85%

“…Reverse transcription was performed using Superscript III (Invitrogen) and oligo (dT) [12][13][14][15][16][17][18] primers, and real-time quantitative PCR was set up containing Power SYBR Green Master Mix (Applied Biosystems, Foster City, CA). The sequences for IGF-1 exon 4-specific primers used are shown in Table 1, and b-actin was used as an endogenous control.…”

Section: Osi-906 Administration To Neonatal Micementioning

confidence: 99%

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Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

Sun¹,

Ramchandran²,

Chen

et al. 2016

Am J Respir Cell Mol Biol

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Insulin-like growth factor (IGF)-1 is a potent mitogen of vascular smooth muscle cells (SMCs), but its role in pulmonary vascular remodeling associated with pulmonary hypertension (PH) is not clear. In an earlier study, we implicated IGF-1 in the pathogenesis of hypoxia-induced PH in neonatal mice. In this study, we hypothesized that hypoxia-induced up-regulation of IGF-1 in vascular smooth muscle is directly responsible for pulmonary vascular remodeling and PH. We studied neonatal and adult mice with smooth muscle-specific deletion of IGF-1 and also used an inhibitor of IGF-1 receptor (IGF-1R), OSI-906, in neonatal mice. We found that, in neonatal mice, SMC-specific deletion of IGF-1 or IGF-1R inhibition with OSI-906 attenuated hypoxia-induced pulmonary vascular remodeling in small arteries, right ventricular hypertrophy, and right ventricular systolic pressure. Pulmonary arterial SMCs from IGF-1-deleted mice or after OSI-906 treatment exhibited reduced proliferative potential. However, in adult mice, smooth muscle-specific deletion of IGF-1 had no effect on hypoxia-induced PH. Our data suggest that vascular smooth muscle-derived IGF-1 plays a critical role in hypoxia-induced PH in neonatal mice but not in adult mice. We speculate that the IGF-1/IGF-1R axis is important in pathogenesis of PH in the developing lung and may be amenable to therapeutic manipulation in this age group.Keywords: insulin-like growth factor; pulmonary hypertension; vascular smooth muscle; neonatal; hypoxia Clinical RelevanceWhat this study adds to the field: Using conditional gene deletion in mice, this study shows that loss of insulin-like growth factor (IGF)-1 in smooth muscle cells protects against hypoxia-induced pulmonary vascular remodeling, right ventricular hypertrophy (RVH), and pulmonary hypertension (PH) in neonatal mice. Inhibition of IGF-1 receptor (IGF-1R) with OSI-906 diminished hypoxia-induced RVH and pulmonary vascular remodeling in neonatal mice, indicating that targeting the IGF-1/IGF-1R axis may have therapeutic benefits in the treatment of hypoxic PH in that age group. Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary arterial pressure accompanied by pulmonary vascular remodeling, leading to right ventricular hypertrophy (RVH) and failure. Proliferation and migration of smooth muscle cells (SMCs) is a characteristic feature of pulmonary vascular remodeling in PH, and dysregulation of many growth factors have been implicated in this process (1, 2). Several growth factors have been implicated in the vascular remodeling and pathogenesis of pulmonary arterial hypertension, and their definitive functions are still being unraveled (reviewed in Refs. 1, 3, 4). Insulin-like growth factor (IGF)-1 is a member of the insulin/IGF family and plays a crucial role in the growth, differentiation, and postnatal development of many tissues and in the regulation of overall growth and metabolism of an organism. IGF-1 is a single-chain polypeptide with a high sequence homology to proinsulin and ...

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Section: Discussionsupporting

confidence: 85%

Section: Osi-906 Administration To Neonatal Micementioning

confidence: 99%

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

Sun¹,

Ramchandran²,

Chen

et al. 2016

Am J Respir Cell Mol Biol

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“…Classical Igf1r-deficient (IGF1R knockout) mice die at birth presumably due to respiratory failure and exhibit a 55 % decrease in body weight compared to wild type controls. Prenatal IGF1R knockout embryos exhibit growth retardation and generalized developmental abnormalities, comprising hypoplasia, altered central nervous system, abnormal skin formation, delayed bone development, reduced pancreatic beta-cells, failure of testicular determination, lung immaturity and cochlear defects (Bonnette and Hadsell 2001;Epaud et al 2012;Liu et al 1993;Nef et al 2003;Okano et al 2011;Scolnick et al 2008;Withers et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice

et al. 2014

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Insulin-like growth factor type 1 receptor (IGF1R) is a ubiquitously expressed tyrosine kinase that regulates cell proliferation, differentiation and survival. It controls body growth and organ homeostasis, but with specific functions depending on developmental time and cell type. Human deficiency in IGF1R is involved in growth failure, microcephaly, mental retardation and deafness, and its overactivation is implicated in oncogenesis. Igf1r-deficient mice die at birth due to growth retardation and respiratory failure. Although multiple Igf1r tissue-specific mutant lines have been analyzed postnatally, using Igf1r-floxed (Igf1r (fl/fl) ) mice mated with diverse cell-type recombinase Cre-expressing transgenics, no mouse models for the study of generalized Igf1r deficiency in adults have been reported. To this end we generated UBC-CreERT2; Igf1r (fl/fl) transgenic mice with an inducible deletion of Igf1r activated by tamoxifen. Tamoxifen administration to 4 week-old prepuberal male mice delayed their growth, producing a distinct impact on organ size 4 weeks later. Whereas testes were smaller, spleen and heart showed an increased organ to body weight ratio. Mosaic Igf1r genomic deletions caused a significant reduction in Igf1r mRNA in all organs analyzed, resulting in diverse phenotypes. While kidneys, spleen and cochlea had unaltered gross morphology, testes revealed halted spermatogenesis, and liver and alveolar lung parenchyma showed increased cell proliferation rates without affecting apoptosis. We demonstrate that UBC-CreERT2 transgenic mice efficiently delete Igf1r upon postnatal tamoxifen treatment in multiple mouse organs, and corroborate that IGF1R function is highly dependent on cell, tissue and organ type.

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“…The lung tissue sections were selected for quantitating airspace in lung. The airspace enragement of the lung was measured using a digitized image tool [17]. The pulmonary inflammation index was graded as previously described [18].…”

Section: Uplc-esi-ms Analysismentioning

confidence: 99%

Galla Chinensis Attenuates Cigarette Smoke‐associated Lung Injury by Inhibiting Recruitment of Inflammatory Cells into the Lung

Lee

Lim

et al. 2014

Basic Clin Pharma Tox

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Inflammation is a common feature in the pathogenesis of cigarette smoke (CS)-associated diseases. In this study, we investigated the effects of Galla Chinensis (GC) extract on pulmonary inflammatory responses in a CS-exposed mouse model. In vitro studies showed that GC extract reduced MCP-1 production in a dose-dependent manner. In addition, the recruitment of inflammatory cells into the lung was significantly inhibited in the bronchoalveolar lavage fluid (BALF) of the GC-treated mice after 3 weeks of daily CS exposure. GC treatment down-regulated TNF-a, IL-6 and MCP-1 mRNA expression levels in lung tissue. Finally, GC-treated mice showed less emphysematous change of alveolar compared to mice only exposed to CS. Our results show that GC extract reduces lung inflammation and emphysematous change by inhibiting the infiltration of inflammatory cells to the lung. These data indicate that GC extract is a therapeutic candidate for CS-induced lung injury.

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Knockout of Insulin-Like Growth Factor-1 Receptor Impairs Distal Lung Morphogenesis

Cited by 64 publications

References 30 publications

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice

Galla Chinensis Attenuates Cigarette Smoke‐associated Lung Injury by Inhibiting Recruitment of Inflammatory Cells into the Lung

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