Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice.

Abstract

Smooth muscle cells (SMC) of the vascular wall, bladder, myometrium, and gastrointestinal and respiratory tracts retain the ability to proliferate postnatally, which enables adaptive responses to injury, hormonal, or mechanical stimulation. SMC growth is regulated by a number of mesenchymal growth factors, including insulin-like growth factor I (IGF-I). To explore the function of IGF-I on SMC in vivo, the mouse SMC ␣ -actin promoter fragment SMP8 ( Ϫ 1074 bp, 63 bp of 5 Ј UT and 2.5 kb of intron 1) was cloned upstream of rat IGF-I cDNA, and the fusion gene microinjected to fertilized eggs of the FVB-N mouse strain. Mating of hemizygous mice with controls produced about 50% transgenic offspring, with equal sex distribution. Transgenic IGF-I mRNA expression was confined to SMC-containing tissues, with the following hierarchy: bladder Ͼ stomach Ͼ aorta ϭ uterus Ͼ intestine. There was no transgene expression in skeletal muscle, heart, or liver. Radioimmunoassayable IGF-I content was increased by 3.5-to 4-fold in aorta, and by almost 10-fold in bladder of transgenic mice at 5 and 10 wk, with no change in plasma IGF-I levels. Wet weight of bladder, stomach, intestine, uterus, and aorta was selectively increased, with no change in total body or carcass weight of transgenic animals. In situ hybridization showed that transgene expression was exquisitely targeted to the smooth muscle layers of the arteries, veins, bladder, ureter, stomach, intestine, and uterus. Paracrine overproduction of IGF-I resulted in hyperplasia of the muscular layers of these tissues, manifesting in remarkably different phenotypes in the various SMC beds. Whereas the muscular layer of the bladder and stomach exhibited a concentric thickening, the SMC of the intestine and uterus grew in a longitudinal fashion, resulting in a marked lengthening of the small bowel and of the uterine horns. This report describes the first successful targeting of expression of any functional protein capable of modifying the phenotype of SMC in transgenic mice. IGF-I stimulates SMC hyperplasia, leading to distinct patterns of organ remodeling in the different tissue environments. (

Impact of Insulin-like Growth Factor-I on Migration, Proliferation and Akt-ERK Signaling in Early and Late-passages of Vascular Smooth Muscle Cells

“…Mean ± SEM, n = 3 independent experiments cultured late passage SMCs exhibit higher proliferation capacity than cells from early passage [20]. IGF-1 has been recognized as an important mitogenic and chemotactic agent for VSMCs [39,40]. Our results indicate that IGF-1 was more effective in inducing migration in the late-passage cells compared to the early passage.…”

Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype

“…Interestingly, QKI is abundantly expressed in these tissues, 40 providing the interesting possibility that, similar to the artery wall, alterations in QKI expression levels could play a regulatory role in pathological complications in these tissues, such as uterine leiomyoma formation, 41 epididymal hyperplasia, 42 and bladder dysfunction. 43,44 In conclusion, our findings imply that QKI is not exclusively associated with neural development and disease, but that QKI is in fact a critical regulator of the functional plasticity that is required for VSMC function under both physiological and pathophysiological conditions.…”

Insulin-like Growth Factor-1 Increases Synthesis of Collagen Type I via Induction of the mRNA-binding Protein LARP6 Expression and Binding to the 5′ Stem-loop of COL1a1 and COL1a2 mRNA

“…Human and mouse IGF-1 levels in serum at time of sacrifice were determined via ELISA (Diagnostic Systems Laboratories, Webster, TX). SMP8-IGF-1 transgenic mice (in an FVB background) were obtained from Dr. James A. Fagin (University of Cincinnati, Cincinnati, Ohio) (22). SMP8-IGF-1 transgene-positive mice (SMP8) were identified by polymerase chain reaction (PCR) and bred to Apoe Ϫ/Ϫ (C57BL/6 background) mice for 8 generations before this line was used for experiments.…”