ATP-sensitive potassium channel activation induces angiogenesis in vitro and in vivo

Intense research is conducted to identify new molecular mechanisms of angiogenesis. Previous studies have shown that the angiogenic effects of hydrogen sulfide (H₂S) depend on the activation of ATP-sensitive potassium channels (K_ATP) and that C-type natriuretic peptide (CNP), which can act through K_ATP, promotes endothelial cell growth. We therefore investigated whether direct K_ATP activation induces angiogenic responses and whether it is required for the endothelial responses to CNP or vascular endothelial growth factor (VEGF). Chick chorioallantoic membrane (CAM) angiogenesis was similarly enhanced by the direct K_ATP channel activator 2-nicotinamidoethyl acetate (SG-209) and by CNP or VEGF. The K_ATP inhibitors glibenclamide and 5-hydroxydecanoate (5-HD) reduced basal and abolished CNP-induced CAM angiogenesis. In vitro, the direct K_ATP openers nicorandil and SG-209 and the polypeptides VEGF and CNP increased proliferation and migration in bEnd.3 mouse endothelial cells. In addition, VEGF and CNP induced cord-like formation on Matrigel by human umbilical vein endothelial cells (HUVECs). All these in vitro endothelial responses were effectively abrogated by glibenclamide or 5-HD. In HUVECs, a small-interfering RNA-mediated decrease in the expression of the inwardly rectifying potassium channel (K_ir) 6.1 subunit impaired cell migration and network morphogenesis in response to either SG-209 or CNP. We conclude that 1) direct pharmacologic activation of K_ATP induces angiogenic effects in vitro and in vivo, 2) angiogenic responses to CNP and VEGF depend on K_ATP activation and require the expression of the K_ir6.1 K_ATP subunit, and 3) K_ATP activation may underpin angiogenesis to a variety of vasoactive stimuli, including H₂S, VEGF, and CNP.