TARGETED OVEREXPRESSION OF IGF-I EVOKES DISTINCT PATTERNS OF ORGAN REMODELING IN SMOOTH-MUSCLE CELL TISSUE BEDS OF TRANSGENIC MICE

Smooth muscle cells (SMC) of the vascular wall, bladder, myometrium, a nd gastrointestinal and respiratory tracts retain the ability to proli ferate postnatally, which enables adaptive responses to injury, hormon al, or mechanical stimulation. SMC growth is regulated by a number of mesenchymal growth factors, including insulin-like growth factor I (IG F-I). To explore the function of IGF-I on SMC in vivo, the mouse SMC a lpha-actin promoter fragment SMPS (-1074 bp, 63 bp of 5'UT and 2.5 kb of intron 1) was cloned upstream of rat IGF-I cDNA, and the fusion gen e microinjected to fertilized eggs of the FVB-N mouse strain. Mating o f hemizygous mice with controls produced about 50% transgenic offsprin g, with equal sex distribution. Transgenic IGF-I mRNA expression was c onfined to SMC-containing tissues, with the following hierarchy: bladd er > stomach > aorta = uterus > intestine. There was no transgene expr ession in skeletal muscle, heart, or liver. Radioimmunoassayable IGF-I content was increased by 3.5- to 4-fold in aorta, and by almost 10-fo ld in bladder of transgenic mice at 5 and 10 wk, with no change in pla sma IGF-I levels. Wet weight of bladder, stomach, intestine, uterus, a nd aorta was selectively increased, with no change in total body or ca rcass weight of transgenic animals. In situ hybridization showed that transgene expression was exquisitely targeted to the smooth muscle lay ers of the arteries, veins, bladder, ureter, stomach, intestine, and u terus. Paracrine overproduction of IGF-I resulted in hyperplasia of th e muscular layers of these tissues, manifesting in remarkably differen t phenotypes in the various SMC beds. Whereas the muscular layer of th e bladder and stomach exhibited a concentric thickening, the SMC of th e intestine and uterus grew in a longitudinal fashion, resulting in a marked lengthening of the small bowel and of the uterine horns. This r eport describes the first successful targeting of expression of any fu nctional protein capable of modifying the phenotype of SMC in transgen ic mice. IGF-I stimulates SMC hyperplasia, Ieading to distinct pattern s of organ remodeling in the different tissue environments.