Cardiac atrial (ANP) and B-type natriuretic peptides (BNP) modulate blood pressure and volume by activation of the guanylyl cyclase-A (GC-A) receptor and intracellular cGMP formation. Here we report a novel function of these peptides as regulators of vascular regeneration.

Arteriogenesis and angiogenesis after critical hindlimb ischemia in mice were assessed by laser-dopper perfusion imaging, magnetic resonance angiography and histology. In mice with systemic deletion of the GC-Agene, vascular regeneration in response to critical hindlimb ischemia was severely impaired. The same attenuation of ischemic angiogenesis was observed in mice with conditional, endothelial-restricted deletion of GC-A. In contrast, smooth muscle-restricted GC-A ablation did not affect ischemic neovascularization. These in vivo studies were complemented with studies on cultured microvascular rat fat pad endothelial cells. ANP and BNP increased endothelial intracellular cyclic GMP levels in a concentration dependent manner. Both natriuretic peptides stimulated endothelial proliferation, migration and angiogenic sprouting. Notably, these responses were nearly as pronounced as the responses to vascular endothelial growth factor (VEGF). Zymographic analyses demonstrated that the stimulatory effects of NP on angiogenesis in vitro were associated with increased endothelial production and secretion of matrix metalloproteinases (MMP), in particular with increased secretion of pro-MMP2. We conclude that endothelial effects of ANP and BNP are critically involved not only in the modulation of systemic blood pressure/volume, but also exert protective effects to enhance postischemic reperfusion and neovascularization. These responses might involve the increased secretion of MMP.

Supported by Deutsche Forschungsgemeinschaft, SFB 688 (to MK), SFB 612 (to UF) and SFB/TR 23(to TW)