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85 TYPE 1 COLLAGEN REGULATES VASCULAR SMOOTH MUSCLE CELL PHENOTYPE BY DOWN-REGULATION OF CREB AND SERUM RESPONSE FACTOR THROUGH AN AKT-DEPENDENT MECHANISM.
  1. Y. Bogaert,
  2. J. Grippa,
  3. R. Nemenoff,
  4. J. E.B. Reusch
  1. Denver VAMC and University of Colorado, Denver, CO

Abstract

Vascular smooth muscle cell (VSMC) differentiation plays an important role in the pathophysiology of atherosclerosis and plaque stability. Previous work has demonstrated that in response to vascular injury, where there is increased production of matrix proteins, VSMCs undergo dedifferentiation as characterized by a switch in phenotype from quiescent and contractile to proliferative and migratory cells. To better understand matrix influence on VSMCs, we cultivated VSMCs on native Type 1 collagen fibrils (NC) or its respective control denatured collagen (DNC). Adult VSMCs on NC showed dramatic decreases in VSMC markers of differentiation, smooth muscle α-actin (SMA) and SM22α. These decreases involved transcriptional control, as there was a significant reduction in their promoter activity. We hypothesized that NC was leading to dedifferentiation of VSMC by decreasing expression of key transcriptional regulators of differentiation-SRF (serum response factor) and CREB (cAMP response element binding protein). To test this hypothesis, VSMCs were plated on NC and DNC. VSMCs on NC had significant decreases in CREB and SRF expression. We investigated the mechanisms involved in decreased SMA and CREB expression on NC. Growth of VSMCs on NC resulted in increased activation of Akt, part of the PI3 kinase signaling cascade, as well as increased platelet-derived growth factor receptor beta expression and activity compared to cells on DNC. Pharmacological disruption of Akt signaling blocked NC down-regulation of SMA and CREB. We next assessed the in vivo relationship between Type 1 collagen, CREB, SRF, and SMA expression. Aortic lysates from fatty Zucker rats at 4 and 14 weeks of age were examined for expression of Type 1 collagen, phospho-Akt, CREB, and SRF by Western immunoblot. Type 1 collagen expression increased in fatty rats by 200% between 4 and 14 weeks, phospho-Akt increased by 80%, CREB content decreased to 60% of baseline, and SRF protein decreased to 20% of baseline. These alterations were prior to changes in SMA.

Summary Exposure of VSMCs to Type 1 collagen correlates with VSMC dedifferentiation both in vivo and in vitro. Accumulation of Type 1 collagen following vascular injury may be an important early mechanism for VSMC dedifferentiation associated with atherosclerotic plaque instability.

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