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Perlecan Heparan Sulfate Is Required for the Inhibition of Smooth Muscle Cell Proliferation by All‐trans‐Retinoic Acid

Smooth muscle cell (SMC) proliferation is a key process in stabilization of atherosclerotic plaques, and during restenosis after interventions. A clearer understanding of SMC growth regulation is therefore needed to design specific anti‐proliferative therapies. Retinoic acid has been shown to inhibit proliferation of SMCs both in vitro and in vivo and to affect the expression of extracellular matrix molecules. To explore the mechanisms behind the growth inhibitory activity of retinoic acid, we hypothesized that retinoids may induce the expression of perlecan, a large heparan sulfate proteoglycan with anti‐proliferative properties. Perlecan expression and accumulation was induced in murine SMC cultures by all‐trans‐retinoic acid (AtRA). Moreover, the growth inhibitory effect of AtRA on wild‐type cells was greatly diminished in SMCs from transgenic mice expressing heparan sulfate‐deficient perlecan, indicating that the inhibition is perlecan heparan sulfate‐dependent. In addition, AtRA influenced activation and phosphorylation of PTEN and Akt differently in wild‐type and mutant SMCs, consistent with previous studies of perlecan‐dependent SMC growth inhibition. We demonstrate that AtRA regulates perlecan expression in SMCs and that the inhibition of SMC proliferation by AtRA is, at least in part, secondary to an increased expression of perlecan and dependent upon its heparan sulfate‐chains. J. Cell. Physiol. 230: 482–487, 2015. © 2014 Wiley Periodicals, Inc.