Cardiac atrial natriuretic peptide (ANP) modulates arterial blood pressure (ABP) by activation of the guanylyl cyclase-A (GC-A) receptor and intracellular cGMP formation. Here we report a novel function of ANP as regulator of vascular regeneration. ANP (1 nM) significantly induced a 20% (at 24 hours) and 52% (at 48 h) increase in the number of cultured bovine aortic endothelial cells at a low concentration of serum. This stimulatory effect was completely blocked by 8 mM Rp-8-Br-PET-cGMPs, an inhibitor of cGMP-dependent protein kinase I. To study whether ANP stimulates endothelial regeneration in vivo, we used a mouse model in which hind limb ischemia was induced by femoral arterial ligation. Blood flow recovery was assessed by Laser Doppler Perfusion Imaging. ABP was measured by tail cuff plethysmography. Synthetic ANP (300 ng/kg BW/min) or vehicle was administered continuously via an osmotic minipump, which was implanted s.c. 3 d after the femoral artery ligation. In wildtype mice, ANP provoked a subtle, reversible drop in ABP by ~ 17 mmHg at 24 h and accelerated postischemic blood flow recovery compared to the vehicle-treated group. In mice with endothelial-restricted deletion of the GC-A receptor, the hypotensive effect of ANP was preserved, but the effect on blood flow recovery was abolished. Our study indicates that ANP not only regulates ABP but also exerts protective effects to enhance postischemic reperfusion and endothelial regeneration. Our observations suggest a therapeutical potential of ANP to treat peripheral arterial diseases refractory to conventional therapies. Supported by SFB 688