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Insulin‐Like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways
Author(s) -
Dempsey Edward C.,
Stenmark Kurt R.,
McMurtry Ivan F.,
O'Brien Richard F.,
Voelkel Norbert F.,
Badesch David B.
Publication year - 1990
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041440121
Subject(s) - growth factor , smooth muscle , microbiology and biotechnology , cell growth , protein kinase a , insulin like growth factor , pulmonary artery , cell , protein kinase c , medicine , signal transduction , kinase , biology , chemistry , endocrinology , biochemistry , receptor
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 (IGF‐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 protein kinase C (PKC)‐indepenent pathway, but that PKC activation would augment this proliferative response. Incorporation of 3 H‐thymidine was used as an index of cellular prohteration, and was correlated with subsequent changes in cell counts. Under serum‐free conditions, IGF‐I (100 ng/ml) 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‐I 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 nM PMA × 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 1 pM, respectively. We conclude that IGF‐I stimulates neonatal PA SMC proliferation via a PKC‐independent pathway, and that trace amounts of PKC activators are capable of synergistically augmenting this response. We speculate that the synergistic stimulation of SMC proliferation by IGF‐I and PKC activators may play an important role in hypertensive pulmonary vascular remodeling.