BAY 41‐2272 reduces vascular smooth muscle cell growth via PK‐G & PK‐A signals

In the cardiovascular system, abnormal growth of vascular smooth muscle (VSM) is intimately involved in both primary disease and during complications following therapeutic intervention. In turn, approaches aimed at modifying the cell signaling pathways responsible for VSM growth are scientifically significant. The objective of the current study is to investigate novel routes for cyclic nucleotide‐based control of VSM growth. We hypothesize that BAY 41‐2272 (BAY), a recently characterized soluble guanylate cyclase (sGC) stimulator and inducer of cyclic guanosine monophosphate (cGMP) synthesis, has capacity to reduce VSM cell proliferation and migration and that these occur through protein kinase‐G (PK‐G) and protein kinase‐A (PK‐A) pathways. In rat thoracic aorta primary VSM cells (passage ≤ 6), BAY reduces proliferation and inhibits migration using a modified Boyden chemotaxis assay and an in vitro scrape wounding injury model. Cyclic nucleotide assays and Western blot analyses reveal that BAY induces both the cGMP and cAMP signaling pathways, and inhibitor studies suggest that BAY operates through both PK‐G and PK‐A. These novel findings show that BAY is capable of reducing VSM growth through stimulation of parallel cGMP and cAMP systems and suggest that BAY may prove therapeutic for the treatment of cardiovascular diseases. Research Support: NHLBI NIH Award Numbers R01HL081720 and R01HL081720‐03S1.