Abstract 19088: Synstatin: A Peptide-Based Switch to Alter the Phenotype of Vascular Smooth Muscle Cells
Introduction: Vascular proliferative diseases such as primary atherosclerosis, postangioplasty restenosis, and transplant vasculopathy reduce the likelihood of success in vascular interventions. The ability of activated vascular smooth muscle cells (vSMCs) to contribute to the vascular lesion mass and to the inflammatory state of the vessel wall after injury is well known. An understanding of the mechanistic basis of vSMC activation can result in more effective therapies for improving vascular outcomes.
Hypothesis: Prior work has suggested that loss of the transmembrane receptor, syndecan-1, can de-differentiate vSMCs. Given the extended reach of the glycosaminoglycan chains of syndecan-1, we hypothesized that the interaction of syndecan-1 with other receptors and matrix molecules can affect vSMC phenotype. It has been identified that the ectodomain of syndecan-1 can regulate the activation of αvβ3 and αvβ5 integrins on mammary carcinoma cells, fibroblasts, and endothelial cells. Further, the peptide synstatin (SSTN) has been found to inhibit this interaction of syndecan-1 with the αvβ3 and αvβ5 integrins. Thus, we further hypothesized that SSTN could modulate vSMC phenotype, affording mechanistic insights into syndecan-1’s role in vSMC differentiation.
Findings: We performed gene expression studies for studying the effect of SSTN addition on the differentiation of primary human aortic SMCs. Real time PCR (n=4) indicated lower levels of smooth muscle-specific differentiation markers [[Unable to Display Character: –]] smooth muscle α-actin, calponin, and smoothelin in SSTN-treated vSMCs. Further, higher levels of the inflammatory markers [[Unable to Display Character: –]] IL-6, ICAM-1, and VCAM-1, and of heparanase, an endoglycosidase which cleaves heparan sulfate (GAG) chains, were observed. This indicates that an SSTN-based tumor stopper, as proposed in literature, could potentially result in vSMC activation and increase the inflammatory state of the blood vessel wall.
Conclusion: Taken together, our results support a positive role for syndecan-1 in promoting vSMC differentiation, reducing the chances of intimal hyperplasia after vascular injury. It also indicates that the interaction of syndecan-1 with the integrins αvβ3 and αvβ5 may be a necessary condition for the differentiation of vSMCs.
- © 2013 by American Heart Association, Inc.