Native and activated forms of α2-macroglobulin increase expression of platelet-derived growth factor α-receptor in vascular smooth muscle cells: Evidence for autocrine transforming growth factor-β activity

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Abstract

Cellular response to platelet-derived growth factor AA (PDGF-AA) is mediated exclusively by the PDGF α-receptor. Vascular smooth muscle cells (VSMCs) in culture typically express very low levels of α-receptor. In this study, we demonstrate that the proteinase inhibitor and cytokine carrier α2-macroglobulin (α2M) increases rat VSMC PDGF α-receptor expression. PDGF α-receptor mRNA levels increased 3-fold by 6 h and were sustained at that level through 24 h in VSMCs treated with 280 nM methylamine-modified α2M (α2M-MA), a form of activated α2M. PDGF β-receptor mRNA levels were unchanged in the same time period. In 125I-PDGF-AA binding experiments, treatment of VSMCs with α2M-MA increased the maximum binding capacity (Bmax) from 1.9 to 9.2 fmol/mg of cell protein without affecting binding affinity (KD ∼ 80 PM). α2M-MA also increased the VSMC response to PDGF-AA as determined by tyrosine phosphorylation of a 170-kDa band, corresponding in mass to the PDGF α-receptor. The native form of α2M was comparable to α2M-MA in its ability to increase PDGF-AA binding to VSMCs and tyrosine phosphorylation of the 170-kDa band. Recombinant and proteolytic α2M derivatives were used to demonstrate that α2M increases PDGF α-receptor expression by binding VSMC-secreted cytokine(s) and interrupting an autocrine loop that ordinarily suppresses α-receptor expression in these cells. Transforming growth factor-β-neutralizing antibody mimicked the activity of α2M, increasing the binding capacity of VSMCs for PDGF-AA. This study demonstrates that VSMC PDGF α-receptor expression and responsiveness to PDGF-AA are regulated by autocrine transforming growth factor-β activity, potentially other autocrine growth factors, and α2M.

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Weaver, A. M., Owens, G. K., & Gonias, S. L. (1995). Native and activated forms of α2-macroglobulin increase expression of platelet-derived growth factor α-receptor in vascular smooth muscle cells: Evidence for autocrine transforming growth factor-β activity. Journal of Biological Chemistry, 270(51), 30741–30748. https://doi.org/10.1074/jbc.270.51.30741

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