Tissue transglutaminase promotes PDGF/PDGFR-mediated signaling and responses in vascular smooth muscle cells

Although the pivotal role of platelet derived growth factor (PDGF)‐mediated signaling in vascular diseases was demonstrated, the pathophysiological mechanisms driving its over‐activation remain incompletely understood. Tissue transglutaminase (tTG) is a multifunctional protein expressed in the vasculature, including smooth muscle cells (SMCs), and implicated in several vascular pathologies. The goal of this study is to define the regulation of PDGF‐BB/PDGFRβ‐induced signaling pathways and cell responses by tTG in vascular SMCs. We find that in human aortic SMCs, shRNA‐mediated depletion and over‐expression of tTG reveals its ability to down‐regulate PDGFRβ levels and induce receptor clustering. In these cells, tTG specifically amplifies the activation of PDGFRβ and its multiple downstream signaling targets in response to PDGF‐BB. Furthermore, tTG promotes dedifferentiation and increases survival, proliferation, and migration of human aortic SMCs mediated by this growth factor. Finally, PDGF‐BB stimulates tTG expression in human aortic SMCs in culture and in the blood vessels in response to injury. Together, our results show that tTG in vascular SMCs acts as a principal enhancer within the PDGF‐BB/PDGFRβ signaling axis involved in phenotypic modulation of these cells, thereby suggesting a novel role for this protein in the progression of vascular diseases. J. Cell. Physiol. 227: 2089–2096, 2012. © 2011 Wiley Periodicals, Inc.