Native and activated forms of alpha 2-macroglobulin increase expression of platelet-derived growth factor alpha-receptor in vascular smooth muscle cells. Evidence for autocrine transforming growth factor-beta activity.

Weaver AM, Owens GK, Gonias SL
J Biol Chem. 1995 270 (51): 30741-8

PMID: 8530514 · DOI:10.1074/jbc.270.51.30741

Cellular response to platelet-derived growth factor AA (PDGF-AA) is mediated exclusively by the PDGF alpha-receptor. Vascular smooth muscle cells (VSMCs) in culture typically express very low levels of alpha-receptor. In this study, we demonstrate that the proteinase inhibitor and cytokine carrier alpha 2-macroglobulin (alpha 2M) increases rat VSMC PDGF alpha-receptor expression. PDGF alpha-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 alpha 2M (alpha 2M-MA), a form of activated alpha 2M. PDGF beta-receptor mRNA levels were unchanged in the same time period. In 125I-PDGF-AA binding experiments, treatment of VSMCs with alpha 2M-MA increased the maximum binding capacity (Bmax) from 1.9 to 9.2 fmol/mg of cell protein without affecting binding affinity (KD approximately 80 pM). alpha 2M-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 alpha-receptor. The native form of alpha 2M was comparable to alpha 2M-MA in its ability to increase PDGF-AA binding to VSMCs and tyrosine phosphorylation of the 170-kDa band. Recombinant and proteolytic alpha 2M derivatives were used to demonstrate that alpha 2M increases PDGF alpha-receptor expression by binding VSMC-secreted cytokine(s) and interrupting an autocrine loop that ordinarily suppresses alpha-receptor expression in these cells. Transforming growth factor-beta-neutralizing antibody mimicked the activity of alpha 2M, increasing the binding capacity of VSMCs for PDGF-AA. This study demonstrates that VSMC PDGF alpha-receptor expression and responsiveness to PDGF-AA are regulated by autocrine transforming growth factor-beta activity, potentially other autocrine growth factors, and alpha 2M.

MeSH Terms (19)

alpha-Macroglobulins Animals Aorta Cell Division Cells, Cultured DNA Fibroblast Growth Factor 2 Gene Expression Humans Kinetics Muscle, Smooth, Vascular Platelet-Derived Growth Factor Rats Rats, Sprague-Dawley Receptor, Platelet-Derived Growth Factor alpha Receptors, Platelet-Derived Growth Factor RNA, Messenger Structure-Activity Relationship Up-Regulation

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