IGF-binding protein-4 expression and IGF-binding protein-4 protease activity are regulated coordinately in smooth muscle during postnatal developmentand after vascular injury

Recent studies support a critical role for the paracrine IGF/IGF-binding pr otein system in the regulation of vascular smooth muscle cell growth. In th is study we have explored the hypothesis that the abundance of individual I GF-binding proteins in smooth muscle is subject to regulation during postna tal life and in response to injury. IGF-binding protein-2 was the predomina nt binding protein secreted by neonatal rat vascular smooth muscle cells, w hereas IGF-binding protein-4 was most prevalent in adult vascular smooth mu scle cells coincident with increased IGF-binding protein-4 protease activit y. After arterial injury, IGF-binding protein-4 mRNA increased, associated with greater IGF-binding protein-4 proteolytic activity, resulting in stabl e steady state levels of the IGF-binding protein-4 protein. Expression of p regnancy-associated plasma protein A mRNA, recently identified as an IGF-bi nding protein-4 protease, was expressed at higher levels in adult than neon atal vascular smooth muscle cell lines, but did not change significantly af ter arterial injury. The peak of immunoreactive pregnancy-associated plasma protein A from hydrophobic interaction chromatography fractions of smooth muscle cell-conditioned medium coincided, but did not fully overlap, with t he fractions containing maximal IGF-binding protein-4 protease activity. In conclusion, our data point to a developmental switch from IGF-binding prot ein-2 to IGF-binding protein-4 in vascular smooth muscle cells postnatally. Moreover, IGF-binding protein-4 expression is coregulated with IGF-binding protein-4 protease activity, suggesting that biosynthesis and degradation of this binding protein are coordinated events important for regulating bio logical activity of IGF-1.