Insulin-Like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways
✍ Scribed by Edward C. Dempsey; Kurt R. Stenmark; Ivan F. McMurtry; Richard F. O'Brien; Norbert F. Voelkel; David B. Badesch
- Publisher
- John Wiley and Sons
- Year
- 1990
- Tongue
- English
- Weight
- 736 KB
- Volume
- 144
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Smooth muscle cell (SMC) hyperplasia is an important component of vascular remodeling in chronic hypoxic pulmonary hypertension. The mechanisms underlying SMC proliferation in the remodeling process are poorly understood, but may involve insulin-like growth factor I (ICF-I). This study investigates the potential proliferative effects of IGF-I on SMC cultured from the pulmonary arteries (PA) of neonatal calves. We hypothesized that IGF-I stimulates PA SMC proliferation through a protcin kinase C (PKC)-independent pathway, but that PKC activation would augment this proliferative response. Incorporation of 'H-thymidine was used as an index of cellular proliferation, and was correlated with subsequent changes in cell counts. Under serum-frce conditions, IGF-I (100 ngiml) induced a 6-fold increase in thymidine incorporation by quiescent PA SMC. This stimulation was not blocked by dihydrosphingosine, an inhibitor of PKC activation. Phorbol myristate acetate (PMA) (1 nM), a membrane-permeable PKC activator, induced a 12-fold increase in thymidine incorporation which was 70% inhibited by dihydrosphingosine. Co-incubation with IGF-l and PMA caused a 60-fold increase in thymidine incorporation, which was 30% inhibited by dihydrosphingosine. This synergistic increase in thymidine incorporation was associated with a subsequent significant increase in cell number. PKC-downregulated cells (1,000 n M PMA x 30 hr) proliferated in response to IGF-I but not PMA, and did not demonstrate synergism with the combination of IGF-I and PMA. The threshold concentrations of IGF-I and PMA for synergism were approximately 1 ng/ml and