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Differential regulation of vascular growth through cGMP/PK‐G/PK‐A signaling
Author(s) -
Joshi Chintamani N,
Martin Danielle N,
Fox Jonathan C,
Adderley Shaquria P,
Tulis David A
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1026.30
Subject(s) - bay , vascular smooth muscle , phosphorylation , cell growth , guanylate cyclase , kinase , chemistry , signal transduction , microbiology and biotechnology , endocrinology , medicine , biology , smooth muscle , biochemistry , receptor , civil engineering , engineering
Vascular smooth muscle (VSM) proliferation and migration are vital components in vessel remodeling. Cyclic nucleotide signaling in cardiovascular tissues is protective and serves as a therapeutic target. The present work analyzed the effects of the recently‐described soluble guanylate cyclase stimulator BAY 41‐2272 (BAY) on vascular growth using a balloon injury model and primary VSM cells. In rat carotid arteries, perivascular application of BAY post‐injury reduced neointimal growth by ~ 40% compared to controls after 2 weeks. In rat primary VSM cells, cyclic GMP content peaked (248x) 20 min after BAY treatment and remained elevated (140x) through 60 min. BAY did not, however, affect cyclic AMP levels or cell viability. In‐Cell Western analyses showed increases in VASP phosphorylation (p‐VASP) at Ser 239 (3x) and Ser 157 (2x), respective markers of cyclic GMP‐ and cyclic AMP‐directed protein kinases. The selective PK‐G inhibitor DT‐2 reversed the BAY‐mediated increase in p‐VASP Ser 239 . BAY (10μM) reduced proliferation by 40% (p<0.05) after 72 h, which was reversed by PKI only. BAY also inhibited PDGF‐induced VSM cell migration by 40% (p<0.001) after 6 h which was completely inhibited by DT‐2. These findings provide direct evidence for PK‐G‐specific anti‐migratory and PK‐A specific anti‐proliferative actions of BAY in VSM, supporting its therapeutic potential in vasoproliferative disorders.