Natriuretic peptides suppress vascular endothelial cell growth factor signaling to angiogenesis

Vascular endothelial cell growth factor (VEGF) is essential for angiogenesi s. Atrial natriuretic peptide (ANP) inhibits the production of VEGF, but wh ether this important vascular peptide also inter- rupts VEGF signaling to a ngiogenesis is unknown. In cultured bovine aortic endothelial cells, VEGF s ignificantly stimulated extracellular signal-regulated protein kinase activ ity and phosphorylation, which was inhibited 60% by coincubation with ANP o r a natriuretic peptide clearance receptor specific ligand (NPRC), C-type N AP-(4-23) [C-ANP-(4-23)]. VEGF also stimulated c-Jun N-terminal kinase (JNK ) and p38 activities/phosphorylation that were prevented by the two natriur etic peptides (NP). A specific NP guanylate cyclase (GC) receptor antagonis t, HS-142-1 , blocked the actions of ANP [but not those of C-ANP-( 4 -23)] supporting the involvement of both GC and NPRC receptors. VEGF and expressi on of constituitively active JNK each stimulated the synthesis of cyclin D1 and increased the activity of the cyclin-dependent kinase-4, which was inh ibited 55% by ANP. VEGF induced endothelial cell proliferation and migratio n, which was significantly blocked by Np or by expressing a dominant negati ve JNK-1. VEGF stimulated human microvascular endothelial cells to form cap illary tubes, which was significantly inhibited by expressing dominant nega tive JNK-1 and by NP. Therefore, VEGF induction of critical steps in angiog enesis is enhanced through JNK activation. The actions are significantly pr evented by NP, which act through both the NPRC and GC receptors to block gr owth factor signaling. Thus, NP are candidate antiangiogenesis factors that inhibit both the synthesis and function of VEGF.